Substituted naphthylene compounds exhibiting selective leukotriene B4 antagonist activity

ABSTRACT

This invention relates to bicyclic aryl compounds having selective LTB 4  antagonist properties and comprising an amido substituent, a substituent group having a terminal carboxylic acid or derivative thereof and a lipophilic substituent, and to methods for the treatment of disorders which result from LTB 4  activity and pharmaceutical compositions including such compounds.

This application is a continuation-in-part application of U.S. Ser. No.07/580,243 filed on Sep. 10, 1990, abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a class of novel compounds useful inthe treatment of a variety of diseases that involve undesirableinflammatory or hypersensitivity responses in diverse animal tissues.Approaches to the treatment of these responses have been as varied asthe tissues in which such responses take place, and include theadministration of antihistamines, analgesics such as aspirin, topicalcoal tar as well as others.

A more recent approach to the moderation of inflammatory andhypersensitivity responses has focused on blocking the action ofarachidonic acid metabolites (including the prostaglandins),lipoxygenases and the leukotrienes. The leukotrienes (LT) metabolitesare formed by oxygenation of a lipoxygenase (5-hydroperoxy-tetraenoicacid (5-HPETE)) which is formed by the specific oxygenation of the C-5position of arachidonic acid. The first leukotriene formed in themetabolic pathway is the unstable epoxide intermediate leukotriene A₄(LTA₄) which is the precursor to the family of peptido-leukotrienes, thefirst in the pathway being LTC₄ which is formed by glutathione addition.LTC₄ is transformed subsequently into LTD₄ and LTE₄ by successiveelimination of a glutamyl and glycine residue. The peptido-leukotrienesprimarily act on smooth muscle and other cells having contractilecapacity, as well as playing a key role in hypersensitivity reactions.In addition, the peptido-leukotrienes are spasmogens, increase vascularpermeability, activate airway smooth muscle, stimulate mucous secretionand are involved with the pathogenesis of certain inflammatory diseasessuch as bronchitis, ectopic and atopic eczema and psoriasis.Leukotrienes appear to be involved in the pathogenesis of asthma such asallergic pulmonary disorders of asthma, hay fever and allergic rhinitis.In addition, LTC₄, LTD₄ and LTE₄ may also decrease blood pressure by anaction on the heart, because they reduce myocardial contractility andcoronary blood flow.

Another family of leukotrienes, LTB₄, is derived from LTA₄ byhydrolase-catalyzed addition of water. This 5, 12-dihydroxy derivativecauses adhesion and chemotactic movement of leukocytes, stimulatesaggregation, enzyme release and generation of superoxide in neutrophils.Additionally, LTB4 is a potent chemotactic and chemokinetic agent foreosinophils, macrophages and monocytes, stimulates suppressor Tlymphocytes and enhances natural cytotoxic cell activity. LTB₄ is also apotent (indirect) bronchoconstrictor but in contrast to thepeptido-leukotrienes C₄, D₄ and E₄ does not appreciably stimulate mucousproduction and induce edema of the airways by increasing vascularpermeability.

2. Reported Developments

It has been suggested that compounds antagonizing LTB₄ activity may bevaluable in the treatment of inflammatory diseases caused by tissuedegrading enzymes and reactive chemicals liberated bytissue-infiltrating and aggregating polymorphonuclear leukocytes. Suchdisease states include inflammatory bowel disease, reperfusion injury,chronic lung diseases, various arthritic conditions, inflammatoryconditions associated with asthma (such as late phase hypersensitivity)and psoriasis.

The literature reports a variety of compounds exhibiting leukotriene B₄antagonist activity. These include compounds having chemical structuresmimicking leukotriene structures such as Sumitomo's SM 9064, UpJohn'sU-75360 and U-75302 and Ciba Geigy's CGS 23113. Other compounds, some ofwhich include monocyclic ring structures and which are disclosed in EP276064, EP 276065 and EP 292977, are reported to exhibit both LTD₄ andLTB₄ antagonist properties.

The present invention is directed to a class of novel bicyclic ringcontaining compounds which exhibit selective LTB₄ antagonist activity.

SUMMARY OF THE INVENTION

This invention relates to compounds having LTB₄ antagonist propertiesand to therapeutic compositions and methods for the treatment ofdisorders which result from LTB₄ activity. In general, this inventioncomprises bicyclic aryl compounds having selective LTB₄ antagonistproperties and comprising an amido substituent, a substituent grouphaving a terminal carboxylic acid or derivative thereof and a lipophilicsubstituent.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As employed above and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

"Bicyclic aryl" means a bicyclic ring system composed of two fused ringswhich may be partially or completely unsaturated carbocyclic and/orheterocyclic rings. Preferred bicycles include naphthalene, indole,benzothiophene, benzofuran, quinoline, chromone and purine.

"Monocyclic aryl" means a partially or completely unsaturatedcarbocyclic or heterocyclic ring. Preferred monocycles include benzene,thiophene, pyridine, furan and pyrimidine.

"Aryl" refers to a partially or completely unsaturated carbocyclic orheterocyclic aromatic ring.

"Alkyl", either alone or with various substituents defined herein, meansa saturated aliphatic hydrocarbon, either branched- or straight-chained.A "loweralkyl" is preferred having about 1 to about 6 carbon atoms.Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, butyl,sec-butyl, t-butyl, amyl and hexyl.

"Alkoxy" refers to a loweralkyl-O-group.

"Alkenyl" refers to a hydrocarbon having at least one point ofunsaturation and may be branched- or straight-chained. Preferred alkenylgroups have 2 to about 6 carbon atoms present. Exemplary alkenyl groupsinclude vinyl, allyl, ethynyl and isopropenyl.

The preferred aryloxy group is phenoxy.

"Aralkyl" means an alkyl group substituted by an aryl radical. Thepreferred aralkyl groups are benzyl or phenethyl.

The preferred aralkoxy groups are benzyloxy and phenethoxy.

"Halo" means a halogen. Preferred halogens include chloride, bromide andfluoride. The preferred haloalkyl group is trifluoromethyl.

More specifically, the bicyclic 6,6 and 6,5 aryl ring systems arepreferred. These are described by formulae I and II ##STR1## where T, U,V and W and T', U', V' and W' are selected from CR₁ R₂, NR₃, O and Sprovided that each ring of said bicyclic systems contain 0-2 heteroatoms and said hetero atoms are not vicinal oxygen and/or sulfur atoms;

X and Z are independently CR₁ R₂, NR₃, O or S;

Y is CR₁ R₂ or NR₃ ; and

R₁ is hydrogen, alkyl or together with a vicinal R₁ may form acarbon-carbon double bond or together with a vicinal R₃ may form acarbon-nitrogen double bond. R₁, R₂ and R₃ are further described below.

Preferred bicyclic ring systems include indene, isoindene, benzofuran,benzothiophene, indole, 1H-indazole, indoline, benzopyrazole,benzoxazole, purine, naphthalene, tetralin, coumarin, chromone,quinoline, isoquinoline, quinazoline, pyrido[3,4-b]pyridine and1,4-benzisoxazine.

Still more preferred compounds are described by Formula II where T, U, Vand W are CR₁ R₂ or NR₃ and T+U+V+W contain no more than 2 NR₃ groups.

Turning now to the three substituents which are necessarily attached tothe bicyclic ring system, the preferred first substituent, which we havecalled the amido function, may be described by formula III: ##STR2##

The preferred second substituent having a terminal carboxylic acid orderivative thereof may be described by formula IV: ##STR3##

The preferred third substituent, the lipophilic substituent, may bedescribed by formula V: ##STR4## where A, B, D, E, F, G, R, R', a, b, d,e, f and g are as described below.

These above substituents of formulae III to V may be attached at variouspositions of the bicyclic ring system and therefore they form part ofthe definition for both R₂ and R₃ and could be present at such sites ofthe bicyclic ring systems defined as CR₁ R₂ or NR₃. When R₂ and R₃ areneither substituent described by Formulae III to V, R₂ may further beselected from hydrogen, alkyl, alkenyl, aryl, aralkyl, alkoxy, aryloxy,aralkoxy, amino, mono- and di-alkylamino, mercapto, alkylthio,aralkylthio, nitro, halo or haloalkyl;

geminal R₁ and R₂ may be =0; and R₃ may further be selected fromhydrogen or alkyl.

The following definitions apply to the substituents of formulae III toV, each of which is attached at a suitable position on the bicyclicring, where:

A is --CRR, O, S, NR', SO or SO₂ ;

B and G are each independently a substituted or unsubstituted monocyclicor bicyclic aryl;

D and F are each independently a bond O, S, NR', SO, SO₂, CONR', NR'CO,--CRR, --O--(CRR)_(j) --, --(CRR)_(j) --O--, --O--(CRR)_(j) --CR═CR--,--CR═CR--(CRR)_(j) --O-- where j is 1-4 or (CR═CR)_(x) where x is 0-2 orC.tbd.C;

E is --COOR', --CONR'R', ##STR5## where y is 2-5, --CN, --CONHSO₂ R',##STR6## tetrazolyl or substituted tetrazolyl where the substituent isalkyl, carboxyalkyl or carbalkoxyalkyl;

R is independently hydrogen or --(CH₂)_(m) --R₂ where m is 0-5 ortogether with a vicinal R group or vicinal R' group forms a 4-7 memberedring which may be saturated or partially unsaturated;

R' is hydrogen, alkyl or aralkyl; and

a, b, d, e, f and g are 0-4 provided d+f+g+x≠0.

The most preferred compounds of this invention are described by thosecompounds of formula II where:

X, Y and Z are CR₁ R₂ or NR₃ provided at least one of X, Y and Z is CR₁R₂ ;

T, U, V and W are CR₁ R₂ or NR₃ provided at least two of T, U, V and Ware CR₁ R₂ ;

R₁ is hydrogen or together with a vicinal R₁ may form a carbon-carbondouble bond or together with a vicinal R₃ may form a carbon-nitrogendouble bond;

R₂ and R₃ are independently hydrogen, and at least one of R₂ and R₃ is##STR7## at least another of R₂ or R₃ is ##STR8## and at least one otherof R₂ and R₃ is ##STR9## where A, B, D, E, F, G, R, R', a, b, d, e, fand g are as described above; and pharmaceutically acceptable saltsthereof.

B and/or G may be optionally substituted with 1 to about 3 R" groupswhere R" is alkyl, haloalkyl, alkoxy, halo or nitro.

A special embodiment of this invention encompasses the compounds offormulae VIa and VIb. ##STR10## where at least one of R₄, R₅, R₆, R₇,R₈, R₉ and R₁₀ and R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈ are ##STR11##at least one of R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ and R₁₁, R₁₂, R₁₃, R₁₄,R₁₅, R₁₆, R₁₇ and R₁₈ are ##STR12## and at least one of R₄, R₅, R₆, R₇,R₈, R₉ and R₁₀ and R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇ and R₁₈ ##STR13##and the remaining R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅,R₁₆, R₁₇ and R₁₈ groups are hydrogen and where:

A is --CRR or O;

B and G are independently phenyl or substituted phenyl where thesubstituents are alkyl, haloalkyl, alkoxy or halo;

D is a bond, O, --CRR, --O--(CRR)_(j--), --(CRR)_(j) --O--,--O--(CRR)_(j) --CR═CR--,--CR═CR--(CRR)_(j) --O-- where j is 1-4 or--(CR═CR)_(x) where x is 1 or 2;

E is --COOR', --CONR'R', ##STR14## where y is 2-5--CN, --CONHSO₂ R',##STR15## tetrazolyl or substituted tetrazolyl where the substituent isalkyl, carboxyalkyl or carbalkoxyalkyl;

F is a bond, O, --CRR, --NR'--(CR═CR)_(x) where x is 0-2;

R is hydrogen or --(CH₂)_(m) --R₂ where m is 0-5;

R₂ is hydrogen, alkyl, alkenyl, phenyl, alkoxy, amino, mono- anddi-alkylamino, mercapto, alkylthio, halo or haloalkyl;

R' is hydrogen, alkyl or aralkyl; and

a, b, d, e, f and g are independently 0-4.

The preferred positions for substitution in the indole molecule offormula VI are the 1, 3, 4 and 5 positions, and the more preferredaspect of this special embodiment includes those compounds where:

A is CHR or O;

B and G are phenyl or substituted phenyl where the substitutents areloweralkyl or loweralkoxy;

D is a O, --CHR, --O--(CRR)_(j) --, --(CRR)_(j) --O--, --O--(CRR)_(j)--CR═CR--, --CR═CR--(CRR)_(j) --O-- where j is 1-4 or (CR═CR)_(x) wherex is 1 or 2;

E is --COOR' or tetrazolyl;

F is a O or --CHR;

R is hydrogen, loweralkyl or aryl;

R' is hydrogen, loweralkyl or arloweralkyl; and

a, b, d, e, f and g are independently 0-4.

Among the most preferred amido substituents are: ##STR16## where R' ishydrogen or lower alkyl and R" is hydrogen, lower alkyl or lower alkoxy.

Among the most preferred terminal acidic substituents are: --(CRR)_(d)--(CRR)_(e) --E where d and e are 0-4, --(CR═CR)_(x) --E where x is 1-2,--O--(CRR)_(j) --(CRR)_(e) --E where j and e are 1-4, --O--(CRR)_(j)--CR═CR--E where j is 1-4 and R is hydrogen or lower alkyl and E is--COOH or ##STR17##

Among the most preferred lipophilic substituents are: ##STR18## where gis 0-4 and R is hydrogen or lower alkyl and R" is hydrogen, lower alkylor lower alkoxy.

While this invention necessitates the presence of three substituentsattached to the bicyclic ring system as described by formulae III to V,it is often desirable to have a fourth substituent present. This may bethe same or different as these already present or it may also be derivedfrom formulae III to V. Other substituents may likewise be desired. Itis to be understood that such compounds fall within the scope of thisinvention.

It may be of interest to one skilled in the art that compounds where Eis OR' may also be of value as LTB₄ antagonists.

The compounds of this invention may be prepared by employing artrecognized procedures from known compounds or readily preparableintermediates. Exemplary general procedures are as follows:

Since the compounds of this invention have three substituents which arenecessarily present, the introduction of each substituent to the arylring system is, of course, dependent on the specific substituentsinvolved and the chemistry necessary for their formation. Thus,consideration of how one substituent would be affected by a chemicalreaction when forming a second substituent would involve techniquesfamiliar to the skilled artisan. This would further be dependent on thebicyclic ring system involved.

It is convenient to synthesize these molecules by employing condensationreactions at reactive A, D and F cites of the molecule. Exemplarygeneral procedures are as follows and are shown for convenience usingthe indole ring system. Of course, while the following reactionsinvolved are basic to developing indole molecules having the threerequired substituents present, the substitution patterns for otherbicyclic rings, such as napthalene, would depend on the chemistry of theparticular ring. Any such adjustments to the chemistry would be familiarto one skilled in the art.

Thus, in order to prepare those compounds where A, D or F is O, S or NR'the following reactions or combination of reactions may be employed:##STR19##

When A, D or F is O or S, the compounds may be prepared by condensationof a bicyclic aryl alcohol or thiol with a compound of the formulae##STR20## where E is preferably a nitrile, ester or tetrazole and L is aleaving group such as halo, tosylate or mesylate. This reaction isusually carried out in the presence of any base normally employed todeprotonate an alcohol or thiol such as sodium hydride, sodiumhydroxide, triethyl amine, sodium bicarbonate, diisopropyl/ethylamine ormethyl magnesium halides.

Reaction temperatures are in the range of room temperature to reflux andreaction times may vary from 2 to 96 hours. The reaction is usuallycarried out in a solvent that will dissolve both reactants and is inertto both as well. Solvents include, but are not limited to diethyl ether,THF, N,N-dimethyl formamide, dimethyl-sulfoxide, dioxane and the like.

When A is an alkyl group, it is convenient to prepare these compounds byFriedel-Crafts alkylation or by the Wittig reaction followed byreduction.

In the case where A, D or F is SO or SO₂, then treatment of the thiocompound with m-chlorobenzoic acid or sodium periodate results in thesulfinyl compound. Preparation of the sulfonyl compound may beaccomplished by known procedures such as dissolving the sulfinylcompound in acetic acid and treating with 30% H₂ O₂.

Those compounds where F and/or D are ##STR21## where x is 1 or 2, areprepared by reacting the appropriate aldehyde or ketone with anappropriate Wittig reagent or modified Wittig reagent of the formula##STR22## where E is cyano or carbalkoxy. Thus for example ##STR23##

Reference for the Wittig reaction and modified Wittig reaction tocontrol the formation of the trans and cis configuration at the doublebond and the isomerization of cis and trans isomers can be found in A.Maercher, Organic Reactions, 14, 270,1965.

The intermediate aldehyde compounds may be prepared in the usual mannerfrom the corresponding carboxylic acid with an alkylithium reagent, orfrom the oxidation of the corresponding alcohol. The aldehyde can alsobe obtained by Friedel-Crafts acylation or formylation (POCl₃ /DMF) ofthe indole, etc.

When F and/or D are ##STR24## then the condensation of an acid or anacid halide with the appropriate aryl amine will give the desiredcompound. ##STR25##

The tetrazoles may be formed from the nitrile at various stages of thesynthesis by treatment with hydrazoic acid formed in situ from sodiumazide and an acid. The nitrile may also be converted to the acids,esters or amides by known methods.

It is convenient to develop the synthesis of the final product bysuccessively forming each desired substituent in turn. Thus in order toprepare a compound such as ##STR26## the following reaction sequencecould be used: ##STR27##

Certain compounds of this invention may have at least one asymmetriccarbon atom such as those compounds having different geminal R groups.Further, certain compounds of this invention may exist in their cis ortrans configuration such as those compounds where D and/or F is CR CR.As a result, those compounds of this invention may be obtained either asracemic mixtures, diastereoisomeric mixtures or as individualenantiomers. The product may be synthesized as a mixture of the isomersand then the desired isomer separated by conventional techniques such aschromatography or fractional crystallization from which eachdiastereomer may be resolved. On the other hand, synthesis may becarried out by known stereospecific processes using the desired form ofthe intermediate which would result in obtaining the desiredstereospecificity.

Reference to the separation of cis and trans isomers by chromatographymay be found in W. K. Chan, et al, J. Am. Chem. Soc. 96, 3642, 1974.

It is to be understood that the scope of this invention encompasses notonly the various isomers which may exist but also the various mixture ofisomers which may be formed.

The resolution of the compounds of this invention and their startingmaterials may be carried out by known procedures. Incorporation byreference is hereby made to the four volume compendium OpticalResolution Procedures for Chemical Compounds: Optical ResolutionInformation Center, Manhattan College, Riverdale, N.Y. Such proceduresare useful in the practice of this invention. A further useful referenceis Enantiomers, Racemates and Resolutions: Jean Jacques, Andre Colletand Samuel H. Wilen; John Wiley & Sons, Inc., New York, 1981. Basically,the resolution of the compounds is based on the differences in thephysical properties of diastereomers. Conversion of the racemates into amixture of diastereomers by attachment of an enantiomerically puremoiety results in forms that are separable by fractionalcrystallization, distillation or chromatography.

The present compounds form salts with acids when a basic amino functionis present and salts with bases when an acid function, i.e., carboxyl,is present. All such salts are useful in the isolation and/orpurification of the new products. Of particular value are thepharmaceutically acceptable salts with both acids and bases. Suitableacids include, for example, hydrochloric, sulfuric, nitric,benzenesulfonic, toluenesulfonic, acetic, maleic, tartaric and the likewhich are pharmaceutically acceptable. Basic salts for pharmaceuticaluse are the Na, K, Ca and Mg salts.

Various substituents on the present new compounds, e.g., as defined inR₂ and R" can be present in the starting compounds, added to any one ofthe intermediates or added after formation of the final products byknown methods of substitution or conversion reactions. If thesubstituents themselves are reactive, then the substituents canthemselves be protected according to the techniques known in the art. Avariety of protecting groups known in the art, may be employed. Examplesof many of these possible groups may be found in "Protective Groups inOrganic Synthesis" by T. W. Green, John Wiley and Sons, 1981. Forexample, nitro groups can be added by nitration and the nitro groupconverted to other groups, such as amino by reduction, and halo bydiazotization of the amino group and replacement of the diazo group.Acyl groups can be added by Friedel-Crafts acylation. The acyl groupscan then by transformed to the corresponding alkyl groups by variousmethods, including the Wolff-Kishner reduction and Clemmenson reduction.Amino groups can be alkylated to form mono- and di-alkylamino groups;and mercapto and hydroxy groups can be alkylated to form correspondingethers. Primary alcohols can be oxidized by oxidizing agents known inthe art to form carboxylic acids or aldehydes, and secondary alcoholscan be oxidized to form ketones. Thus, substitution or alterationreactions can be employed to provide a variety of substituentsthroughout the molecule of the starting material, intermediates, or thefinal product.

Compounds within the scope of the present invention have potent activityas leukotriene B₄ antagonists and as such possess therapeutic value inthe treatment of inflammatory conditions and hypersensitivity responses.LTB₄ is implicated in diseases such as rheumatoid arthritis, gout,psoriasis and inflammatory bowel disease and therefore compounds whichdemonstrate LTB₄ antagonist properties would be of valuable in thecontrol of these states.

The LTB₄ guinea pig polymorphonuclear membrane binding assay can be usedto determine compounds exhibiting LTB₄ receptor binding properties.Compounds active in this assay can then be subjected to the guinea pigperitoneal PMN LTB₄ -induced aggregation assay. THE LTB₄ -inducedaggregation assay determines the antagonistic activity of a compound.The guinea pig LTB₄ -induced wheal assay is used to determine in vivoactivity.

Assay for Inhibitors of (³ H)-LTB₄ Binding to Membranes From Guinea PigPolymorphonuclear Leukocytes

Preparation of test compounds

Dissolve compounds to a concentration 100-fold higher than the highestdesired concentration for testing. Serially dilute the compound so thatall dilutions are 100-fold higher than the assay concentration desired.Compounds are typically dissolved in DMSO. If compounds are insoluble inDMSO, solutions are heated or sonicated to induce solubilization.Compounds may also be dissolved in ethanol.

Final assay concentrations of DMSO and ethanol can be as high as 1.0%and 2.0% (v/v); these concentrations have no measurable effects onspecific binding.

Preparation of the membrane receptor fraction

To obtain polymorphonuclear leukocytes (PMNs), 25-30 male Hartley guineapigs (250-350 g) are intraperitoneally injected with 6 mls of an 8%sodium caseinate solution. 18 to 24 hours later, the guinea pigs aresacrificed by decapitation. The peritoneal cavity is lavaged with 15 mlsof isolation buffer. The cells are collected and centrifuged at 200×gfor 10 minutes. Contaminating red blood cells can be removed byhypotonic lysis. The cells are resuspended in isolation buffer andcentrifuged as before. They are filtered through gauze and centrifugedagain. The resulting pellet is suspended in 3 ml of sonication buffer,counted and brought to a concentration of 1×10⁸ cells/ml. Thissuspension is lysed on ice with 5 bursts of 30 seconds separated by 1minute intervals. The homogenate is centrifuged at 200×g for 10 minutesat 4° C. Aliquots of supernatant are transferred to high speedcentrifuge tubes (1 tube per 3 guinea pigs). The tubes are centrifugedat 49,000×g for 15 minutes at 4° C. The pellets are resuspended by three5 second bursts of sonication, separated by 20 second intervals. Thissuspension is centrifuged at 50,000×g for 20 minutes at 4° C. Pelletsare stored at -70° C. for up to 3 months.

To use in the binding assay, the pellet is thawed at room temperatureand suspended in 9 mls of assay buffer (sonication may be necessary).

Binding assay

Each assay tube (16×100 mm) contains the following:

345 μl Assay Buffer

5 μl Test compound or solvent

50 μl ³ H-LTB₄ (0.50 nM)

100 μl Protein preparation (0.2 mg)

Incubations are done at 30° C. for 40 minutes in a water bath. Reactionsare started by the addition of (³ H)-LTB₄ solution. Samples arecollected via a Brandel M24 Harvester for binding assays. Tubes shouldbe washed with a total of 19 ml cold wash buffer.

The filters are transferred to 7 ml plastic scintillation vials to which6.0 ml of appropriate scintillation fluid (e.g., Scintiverse®) is added.After being allowed to equilibrate for 12 hours, the radioactivity iscounted with a liquid scintillation counter appropriately set fortritium.

The required control assay tubes include the following:

(a) Total Binding: No test compound is added; buffer is substituted.

(b) Non-Specific Binding: Non-labeled ligand is added at a concentrationof 1 μM.

(c) Solvent Controls: If test compound is dissolved in a solvent,controls for both Total Binding and Non-Specific Binding containingsolvent but no compounds are required.

Calculations:

Specific binding is defined as that amount of radioligand prevented frombinding by 1000-fold excess non-labeled ligand, i.e., total bindingminus non-specific binding. This operational definition is verified byScatchard analysis of total binding.

Inhibition of specific binding is defined as the decrease in specificbinding caused by the test compound, ##EQU1## where SB_(C) is thespecific binding in the absence of test compound and SB_(T) is thespecific binding in the presence of test compound. The I₅₀ values(concentrations required to inhibit specific binding by 50%) aredetermined by graphic analysis of the specific binding observed in thepresence of various concentrations of test compound.

The results of this test indicate that compounds of this inventionexhibit valuable LTB₄ receptor binding properties which are useful inthe treatment of inflammatory conditions and hypersensitivity responses.

LTB₄ -Induced Wheal Formation in Guinea Pig

LTB₄ plays the role of a mediator in cellular induced inflammation. Theinduction of chemokinesis and chemotaxis of PMNs and macrophage by LTB₄have contributed to its association with the vascular aspects of acuteinflammatory reactions.

In this test intradermal injection of 0.1 ml of a 10 μg/ml solution ofLTB₄ to guinea pig back skin causes the formation of a wheal. This whealis visualized by the prior intravenous injection with the indicator 1%Evan's Blue dye. Following a 2 hour incubation post-LTB₄ challenge, theguinea pigs are euthanized via CO2 asphyxiation. Their dorsal skins arereflected and the diameters of the challenged sites are compared withthose of the vehicle control injected sites.

Preparation and handling of guinea pigs

The guinea pigs must be quarantined 5 to 7 days prior to the study. Theday before the test, the back and hind limbs are shaved taking care notto nick the skin. After shaving, the guinea pigs are fasted, but wateris provided.

On the day of the test, the guinea pigs are weighed and identified withan ink mark designating them with numbers 1 through 5 in each group.Groups are formed by random distribution.

Preparation and route of administration of compounds

The oral vehicles are Polyethylene Glycol (PEG 400) (2 ml/kg) andmethocel (0.5% w/v) (10 ml/kg). Exposure to the ultrasound of a Bransonsonicator assures uniformity of suspension or dissolution of the testcompounds. Compounds for parenteral administration are dissolved insaline with the assistance of 0.1N HCl and 0.1N NaOH and then adjustingthe pH to near neutrality.

Although test compounds are usually administered orally, other routes ofadministration such as intravenous, intraperitoneal or subcutaneous maybe

Preparation of leukotriene B₄ for intradermal injection used.

LTB₄ is obtained as a stock solution (50 μg/ml) in ethanol and is storedat -80° C. until required for use. The stock solution or an appropriatealiquot is transferred from the ampule into a 10 ml glass vial using apasteur pipette. The stock solution is then evaporated to dryness undera slow, steady stream of argon gas.

A solution of freshly prepared 0.25% Bovine Albumin inPhosphate-Buffered Saline is bubbled with argon gas until the saturationpoint is reached (approximately 5 minutes). This argon-saturated vehicleis then used to reconstitute the evaporated LTB₄ stock residue to yielda final working concentration of 10 μg/ml. The rubber stoppered vial ofLTB₄ working solution is kept on wet ice during the study.

Preparation of Evan's Blue dye solution

Because Evan's Blue is an easily visible marker that binds to the plasmaproteins, it has been selected to assist the investigator in themeasurement of the wheals induced during the study. Evan's Blue Dye isdissolved as a 1% w/v solution in 0.9% w/v physiologic saline. Thenumber of 1 ml plastic disposable syringes, fitted with 27 gauge, 1/2inch needles and filled with the 1% dye solution, is determined by thenumber of animals expected to be included in the study.

Conduct of an experiment

Test compounds or their appropriate controls are administered orallywith 16 gauge, 3 inch dosing cannulas. Immediately after dosing, theguinea pig is injected intravenously with 1 ml of 1% Evan's Blue Dyeinto a digital vein in the left or right shaved hind limb. Thisinjection is facilitated best through the use of a 1 ml plastic syringefitted with a 27 gauge, 1/2 inch needle. Immediately following Evan'sBlue injection, the guinea pig is injected intracutaneously at each of 2sites in the shaved dorsal midline with 0.1 ml of the preparedargon-saturated LTB₄ solution (1 μg/0.1 ml). A third site isintracutaneously injected with the argon-saturated 0.25% bovine albuminin phosphate-buffered saline to serve as a vehicle control.

2 hours after challenge, the guinea pigs are euthanized by inhalation ofcarbon dioxide. Carbon dioxide is administered by inserting a rubbertube from the tank into a plastic bag containing the caged group ofguinea pigs. Asphyxiation occurs in approximately 5 minutes.

After death, the dorsal skins are reflected to enable the measurement of2 perpendicular diameters of the resultant wheals. The area of eachwheal is determined using the formula: Area=πr².

Calculations and statistics

For each guinea pig, the mean of the wheal areas obtained for the 2injections sites is established after correction is made for the effectof the wheal area induced by the 0.25% Bovine Albumin inPhosphate-Buffered Saline vehicle. Then, a mean area for each treatmentgroup with its corresponding standard error is calculated.

The following equation is used to calculate the percent inhibition ofvehicle treated control wheal area by treatment with test compound:##EQU2##

In multiple dose experiments, the dose of a test compound that willcause 50% inhibition (ED₅₀) can be calculated from the regressionequation for the response as percent inhibition (y) and log dose (x) andestimating the (ED₅₀) from: y(50)=bx+m where:

y=50% inhibition,

x=dose of test compound,

b=slope of dose response line and

m=intercept of the dose response line.

95% confidence limits of ED₅₀ are calculated from the regressionequation by the method of Litchfield and Wilcoxon where: ##EQU3## whereS is the slope function used to compute the limit factor fED₅₀ 2.77/√Nas fED₅₀ =S. 2.77 is an estimator, N is the square root of the number ofanimals used for all the doses and fED₅₀ is the factor to determine theupper (RU) and lower (RL) limits of the ED₅₀ as: RU=ED₅₀ ×fED₅₀ andRL=ED₅₀ ÷fED₅₀. Statistical significance of any inhibition caused bytreatment with a test compound can be calculated by applying Student's t(two-tailed) to the data.

Validation and specificity studies

The 1 μg/0.1 ml/site challenge dose of LTB₄ was selected for thereproducibility, sensitivity and ease of measurement of the resultantwheal. Studies have indicated that size of wheals induced by LTB₄ isdirectly related to the dose administered.

2 hours of incubation after intradermal challenge with LTB₄ was selectedas the routine timing for the study. Duration studies conductedevidenced the production of measurable, reproducible wheals at the 2hour endpoint.

In view of the results obtained when compounds of the present inventionare subjected to this test, it can be demonstrated that valuableproperties as LTB₄ antagonists are indicated.

A further test which may be used to determine the ability of compoundsof this invention to exhibit LTB₄ antagonist activities is as follows:

Guinea Pig Polymorphonuclear Leukocyte Aggregation Assay

Isolation of guinea pig PMNs

6 ml of 6% Na-caseinate (in saline) is injected intraperitoneally into 2male guinea pigs (250-300 g) lightly anesthetized with CO₂ or ether. Thefollowing day (18-24 hours post injection) the animals are sacrificed bydecapitation or CO₂ overdose according to the SOP for nonclinicallaboratory study methods.

A midline section of abdominal skin is removed and 13 ml Hanks buffer(containing 500 μl 10 mM EDTA/500 ml Hanks) plus 2 ml 7% Na-citrate isinjected into the peritoneal cavity. The guinea pig is rocked back andforth 5 times. A small incision is made on the left side of the midlineof the abdominal wall (avoid cutting obvious blood vessels). Use afire-polished pasteur pipette to transfer the buffer plus cells from theabdominal cavity to 2 washed Nalgene (Oak Ridge) centrifuge tubes (halfof buffer and cells in each tube). The tubes are then filled to 50 mlwith additional citrate-Hanks buffer and centrifuged at 4000 rpm for 10minutes.

Each pellet is resuspended in 1 ml of citrate-Hanks and then diluted to50 ml with the same buffer. The cells are incubated for 30 minutes atroom temperature on a Hema-Tek aliquot mixer. The cells are filteredthrough 2 layers of gauze into 50 ml with plastic beakers to remove PMNaggregates and then transferred to fresh, washed, 50 ml Nalgenecentrifuge tubes.

The cells are centrifuged for 5 minutes, resuspended in 50 ml of freshbuffer, centrifuged again and then resuspended in 3 ml of citrate-freeHanks buffer. (Following any centrifugation the cells are alwaysresuspended first in 1 ml of the desired fresh buffer.)

An aliquot of the washed cells, diluted 50-fold, is counted using amicroscope and a hemacytometer.

The PMNs are counted as follows:

1. Dilute 50 μl of cells into 450 μl of Hank's buffer.

2. Dilute 50 μl of (1) with 150 μl of Hank's buffer plus 50 μl ofToluidine blue (50× total dilution). Add 10 μl of (2) to thehemacytometer and count cells in 16 large squares (volume counted =1μl). View the hemacytometer under 40× magnification. The unstained cellsare PMNs. Calculation: Assume 149 cells are counted. ##EQU4##

Thus, cells must be diluted 2.48-fold with Hanks buffer (2.48×3=7.44 ml;7.44 -3.0=4.44; add 4.44 ml buffer to the 3 ml of washed cells). Thisresults in 7.44 ml of cells at a concentration of 3×10⁷ cells per ml.

Instrument adjustments

Place cuvettes containing 1×10⁷ cells/ml (166 μl PMNs plus 334 μlbuffer) plus flea magnets in the aggregometer sample wells. Turn on theChart Advance to 30 cm/hr. Turn the attenuation dials to mid range anddecrease the recorder mV range settings to 50 mV full scale. Press thered "zero" button on the aggregometer and note exactly the position ofthe recorder pens. Turn the aggregometer left hand "PPP" dials for eachcuvette position to the left or right so that the associated recorderpens move to the exact positions noted by pressing the red "zero"button. The electrical circuits are now "balanced". Except for smallbalance adjustments, do not make any further changes in pen positions byadjusting the "PPP" dials.

Withdraw one of the cuvettes from the aggregometer and note the(positive) direction of recorder pen motion. Replace the cuvette. Usingthe recorder zero knob, move the recorder pen in the positive directionto the chart paper 95% line. The pens now should not move when the red"zero" button is pressed. The pen also should not move when the mVsensitivity range is changed to 20 or 10 mV full scale (leave at 10 mV).

PMN aggregation should cause the pen to move in the "negative" directionacross the chart paper. Make comparable adjustments for the secondaggregometer channel but zero the recorder pen on the opposite side ofthe chart paper. Finally, pressing the zero button on either therecorder or the aggregometer should not cause the pens to move more thana mm or two. This instrument configuration will result in maximal pendeflection following aggregation of cells.

Aggregation studies

To a cuvette containing 334 μl of buffer and a flea magnet, add 166 μlof PMNs, 10 μl of Ca⁼⁼ /Mg⁺⁺ (70/et mM; 1.4/0.7 mM final) and 5 μl of 10μM cytochalasin-β allow to warm up in the aggregometer (37° C.) for 5minutes and then add 1 μl of test compound in DMSO or DMSO carrieralone. Note compound effects, if any, for 2 minutes, then add 5 μl ofthe challenge agonist (LTB₄, PAF, etc.) and observe the response for atleast 2 minutes. The standard concentrations of agonists used in thisassay are arachidonic acid, 6 μM; LTB₄, 0.3 nM; PAF, 30 pM; and FMLP,0.6 nM.

Aggregation is quantitated by measuring, in millimeters, the averagemaximum deflection of the pen line at 1 minute or less after theaddition of LTB₄. The maximum response to a control challenge witharachidonic acid may develop somewhat more slowly than this.

Each aggregometer-recorder channel should include its own series ofcontrol aggregations. All compounds should be tested at least twice ateach concentration of interest. The inhibitory activity observed isexpressed as the mean percent change (inhibition) observed relative tothe controls determined in that channel. Controls must includeappropriate solvent blanks.

The results of the above test demonstrate that compounds within thescope of this invention inhibit the activity of LTB₄.

The compounds of the present invention can be administered to amammalian host in a variety of forms adapted to the chosen route ofadministration, i.e., orally, or parenterally. Parenteral administrationin this respect includes administration by the following routes:intravenous, intramuscular, subcutaneous, intraocular, intrasynovial,transepthelially including transdermal, ophthalmic, sublingual andbuccal; topically including ophthalmic, dermal, ocular, rectal and nasalinhalation via insufflation and aerosol and rectal systemic.

The active compound may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or it may beenclosed in hard or soft shell gelatin capsules, or it may be compressedinto tablets, or it may be incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with excipient and used in the form of ingestible tablets,buccal tablets, trochees, capsules, elixirs, suspensions, syrups,wafers, and the like. Such compositions and preparations should containat least 0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 6% of the weight of the unit. The amount of activecompound in such therapeutically useful compositions is such that asuitable dosage will be obtained. Preferred compositions or preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between about 50 and 300 mg of active compound.

The tablets, trochees, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carder. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or both. A syrup or elixir may contain the active compound,sucrose as a sweetening agent, methyl and propylparabens apreservatives, a dye and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed. In addition, the active compound may be incorporated intosustained-release preparations and formulations.

The active compound may also be administered parenterally orintraperitoneally. Solutions of the active compound as a free base orpharmacologically acceptable salt can be prepared in water suitablymixed with a surfactant such as hydroxy-propylcellulose. Dispersion canalso be prepared in glycerol, liquid polyethylene glycols, and mixturesthereof and in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that easy syringability exists. It may be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarder can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), suitable mixtures thereof,and vegetable oils. The proper fluidity can be maintained, for example,by the use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions of agents delaying absorption, for example,aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and the freeze dryingtechnique which yield a powder of the active ingredient plus anyadditional desired ingredient from previously sterile-filtered solutionthereof.

The therapeutic compounds of this invention may be administered to amammal alone or in combination with pharmaceutically acceptablecarriers, as noted above, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard pharmaceutical practice.

The physician will determine the dosage of the present therapeuticagents which will be most suitable for prophylaxis or treatment and itwill vary with the form of administration and the particular compoundchosen, and also, it will vary with the particular patient undertreatment. He will generally wish to initiate treatment with smalldosages by small increments until the optimum effect under thecircumstances is reached. The therapeutic dosage will generally be from0.1 to 100 M/day or from about 0.1 mg to about 50 mg/kg of body weightper day and higher although it may be administered in several differentdosage units. Higher dosages are required for oral administration.

The compounds of the present invention may be prepared by the followingrepresentative examples:

Example 1 N-methyl-N-phenethyl-2-bromoacetamide

To a solution of 27.07 g (171.95 mmol) of bromoacetyl chloride in 100 mlof methylene chloride, cooled to -25° C. by means of an external coolingbath, is added dropwise a solution of 46.5 g (343.9 mmol) ofN-methyl-N-phenethyl amine in 50 ml of methylene chloride over a periodof 11/2 hours. The reaction mixture is stirred at -25° C. for additional15 minutes and then allowed to equilibrate to room temperature. Thereaction mixture is then partitioned between methylene chloride andwater. The organic layer is washed with 1N aqueous HCl solution andwater, dried over magnesium sulfate and concentrated in vacuo to giveN-methyl-N-phenethyl-2-bromoacetamide which is used directly in the nextstep.

Example 2 5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole

A mixture of 1 g (7.29 mmol) of 5-hydroxyindole, 2.42 g (9.4 mmol) ofN-methyl-N-phenethyl-2-bromoacetamide and 1.06 g of finely groundanhydrous potassium carbonate in 20 ml of 2-butanone is heated to agentle reflux for 18 hours. After cooling to room temperature, the solidsubstance is filtered off and the filtrate concentrated in vacuo to give3 g of the crude product. Purification by dry column chromatography oversilica gel eluting with a solvent system of ethyl acetate/hexane (1:1,v/v) gives 5-[2-(N-methyl-N-phenethyl)-amino-2-oxo]ethoxyindole. NMRconfirms this structure.

Example 3 5-benzyloxyindole 5-(4-methylbenzyloxy)indole

When N-methyl-N-phenethyl-2-bromoacetate is replaced in the procedure ofExample 2 with α-bromotoluene or α-bromo-p-xylene then the productsprepared are 5-benzyloxyindole or 5-(4-methylbenzyloxy)indole. NMRconfirms these structures.

Example 4 6-benzyloxyindole 6-(4-methylbenzyloxy)indole

When 5-hydroxyindole is replaced in the procedure of Example 3 with6-hydroxyindole then the products prepared are 6-benzyloxyindole and6-(4-methylbenzyloxy)indole. NMR confirms these structures.

Example 5 6-[2-(N-methyl-N-phenethyl)amino-2-oxolethoxyindole

When 5-hydroxyindole is replaced in the procedure of Example 2 with6-hydroxyindole then the product prepared is6-[2-(N-methyl-N-phenethyl)-amino-2-oxo]ethoxyindole.

Example 65-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole-3-carboxaldehyde

To 2.4 ml of N,N-dimethylformamide, stirred under nitrogen in a coolingbath of 10°-20° C. is added dropwise 0.76 ml of phosphorous oxychloride.The mixture is stirred for an additional 10 minutes and a solution of2.2 g of N-methyl-N-phenethyl-2-(5-indolyloxy)acetamide in 6.5 ml ofN,N-dimethylformamide is added dropwise. The reaction mixture is stirredat room temperature for 50 minutes and poured into 45 ml of an ice-watermixture with stirring. The mixture is adjusted to pH 7 with aqueoussodium hydroxide solution, heated in a water bath of 95° C. for threeminutes and allowed to cool to room temperature. Ethyl acetate is addedand the layers separated. The organic layer is washed with a smallamount of 1N aqueous HCl solution and several times with brine, driedover magnesium sulfate and concentrated in vacuo. The residue ispurified by dry column chromatography over silica gel eluting with asolvent system of 10% ethyl acetate in hexane to afford5-[2-(N-methyl-N-phenethyl)amino-2-oxo] ethoxyindole-3-carboxaldehyde asa beige solid substance. NMR confirms this structure.

Example 7 5-benzyloxyindole-3-carboxaldehyde5-(4-methylbenzyloxylindole-3-carboxaldehyde

When N-methyl-N-phenethyl-2-(5-indolyloxy)acetamide is replaced in theprocedure of Example 6 with 5-benzyl-oxyindole and5-(4-methylbenzyloxy)indole then the products obtained are5-benzyloxyindole-3-carboxaldehyde and5-(4-methylbenzyloxy)indole-3-carboxaldehyde. NMR confirms thesestructures.

Example 8 6-benzyloxyindole-3-carboxaldehyde6-(4-methylbenzyloxy)indole-3-carboxaldehyde

When N-methyl-N-phenethyl-2-(5-indolyloxy)acetamide is replaced in theprocedure of Example 6 with 6-benzyl-oxyindole and 6-(4-methylbenzyloxy)indole then the products obtained are6-benzyloxyindole-3-carboxaldehyde and6-(4-methylbenzyloxy)indole-3-carboxaldehyde.

Example 96-2-N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole-3-carboxaldehyde

When N-methyl-N-phenethyl-2-(5-indolyloxy)acetamide is replaced in theprocedure of Example 6 withN-methyl-N-phenethyl-2-(6-indolyloxy)acetamide then the product preparedis 6-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole-3-carboxaldehyde.

Example 10N-methyl-N-phenethyl-2-(5-benzyloxy-3-formyl)indol-1-yl]acetamide

To a suspension of sodium hydride (615 mg, 80% dispersion in mineraloil, 20.5 mmol) in 90 ml of tetrahydrofuran, cooled to 0° C. by means ofan external ice bath, is added in portions 4.9 g (19.52 mmol) of5-benzyl-oxyindole-3-carboxaldehyde. The reaction mixture is stirred inthe ice bath for an additional 10 minutes and 5 g (19.52 mmol) ofN-methyl-N-phenethyl-2-bromoacetamide added. The resulting mixture isstirred at room temperature for 18 hours.

The reaction mixture is filtered through Cellite® to remove theprecipitate and the filtrate concentrated in vacuo to give an oilysubstance. Purification of this crude product by chromatography oversilica gel eluting with a solvent system of methylene chloride/ethylacetate (2:1, v/v) givesN-methyl-N-phenethyl-2-[(5-benzyloxy-3-formyl)indol-1-yl]acetamide as awhite powder (m.p. 78°-80° C.).

Example 11N-methyl-N-phenethyl-2-(6-benzyloxy-3-formyl)indol-1-yl]acetamide

When 5-benzyloxyindole-3-carboxaldehyde in the procedure of Example 10is replaced by 6-benzyloxyindole-3-carboxaldehyde then the compoundprepared isN-methyl-N-phenethyl-2-[(6-benzyloxy-3-formyl)indol-1-yl]acetamide. NMRconfirms structure.

Example 12N-methyl-N-phenethyl-2-[(5(2-methylphenethylamino-2-oxo)ethoxy-3-formyl)indol-1-yl]acetamide

When 5-benzyloxyindole-3-carboxaldehyde in the procedure of Example 10is replaced by5-[2-(N-methyl-N-phenethyl)amino-2-oxo]-ethoxyindole-3-carboxaldehydethen the product prepared isN-methyl-N-phenethyl-2-[(5-(2-methylphenethylamino-2-oxo)ethoxy-3-formyl)indol-1-yl]acetamide.

Example 13 N-methyl,N-phenethyl-2-[(6-(2-methylphenethylamino-2-oxo)ethoxy-3-formyl)indol-1-yl]acetamide

When 5-benzyloxyindole-3-carboxaldehyde in the procedure of Example 10is replaced by6-[2-(N-methyl-N-phenethyl)amino-2-oxo]-ethoxyindole-3-carboxaldehydethen the product prepared isN-methyl-N-phenethyl-2-[(6-(2-methylphenethylamino-2-oxo)ethoxy-3-formyl)indol-1-yl]acetamide.

Example 14 N-methyl-N-(4-methoxy)phenethyl-2-bromoacetamide

A mixture of 0.55 g of N-methyl-N-(4-methoxy)-phenethylamine, 0.51 g ofbromoacetic acid and 1.56 g of1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonatein 10 ml of methylene chloride is stirred at room temperature for 48hours. The reaction mixture is filtered and the filtrate is concentratedin vacuo to give an oily residue. Purification of the residue by drycolumn chromatography over silica gel eluting with a solvent system ofhexane/ethyl acetate (2:1, v/v) gives 0.884 g ofN-methyl-N-(4-methoxy)phenethyl-2-bromoacetamide as a beige oil. NMRconfirms this structure.

Example 15N-(4-methoxy)phenethyl-N-methyl-2-[(5-benzyloxy-3-formyl)indol-1-yl]acetamide

When N-methyl-N-phenethyl-2-bromoacetamide in the procedure of Example10 is replaced by N-methyl-N-(4-methoxy)phenethyl-2-bromoacetate thenthe product prepared isN-(4-methoxy)phenethyl-N-methyl-2-[(5-benzyloxy-3-formyl)indol-1-yl]acetamide.NMR confirms this structure.

Example 16 2-methyl-4-benzyloxyindole 7-benzyloxyindole

When 5-hydroxyindole in the procedure of Example 3 is replaced with2-methyl-4-hydroxyindole or 7-hydroxyindole then the products preparedare 2-methyl-4-benzyloxyindole and 7-benzyloxyindole.

Example 17 2-methyl-4-benzyloxyindole-3-carboxaldehyde7-benzyloxyindole-3-carboxaldehyde

When 5-benzyloxyindole in the procedure of Example 7 is replaced by2-methyl-4-benzyloxyindole and 7-benzyloxy-indole then the productsprepared are 2-methyl-4-benzyl-oxyindole-3-carboxaldehyde and7-benzyloxyindole-3-carboxaldehyde.

Example 18N-methyl-N-phenethyl-2-[(4-benzyloxy-3-formyl)indol-1-yl]acetamide

When 5-benzyloxyindole-3-carboxaldehyde in the procedure of Example 10is replaced by 4-benzyloxyindole-3-carboxaldehyde then the productprepared isN-methyl-N-phenethyl-2-[(4-benzyloxy-3-formyl)indol-1-yl]acetamide.

Example 19N-methyl-N-phenethyl-2-[(7-benzyloxy-3-formyl)indol-1-yl]acetamide

When 5-benzyloxyindole-3-carboxaldehyde in the procedure of Example 10is replaced by 7-benzyloxyindole-3-carboxaldehyde then the productprepared isN-methyl-N-phenethyl-2-[(7-benzyloxy-3-formyl)indol-1-yl]acetamide. NMRconfirms this structure.

Example 20N-methyl-N-phenethyl-2-[(5-(4-methylbenzyloxyl)-3-formyl)indol-1-yl]acetamide

When 5-benzyloxyindole-3-carboxaldehyde in the procedure of Example 10is replaced by 5-(4-methyl-benzyloxy)indole-3-carboxaldehyde then theproduct prepared isN-methyl-N-phenethyl-2-[(5-(4-methylbenzyloxy)-3-formyl)indol-1-yl]acetamide.NMR confirms this structure.

Example 211-benzyl-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole-3-carboxaldehyde

When N-methyl-N-phenethyl-2-bromoacetamide in the procedure of Example12 is replaced by benzyl bromide then the compound prepared is1-benzyl-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole-3-carboxaldehyde.NMR confirms this structure.

Example 22N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamide

To a suspension of NaH (1.68 g, 80% dispersion in mineral oil, 56 mmol)in 150 ml of tetrahydrofuran, stirred in an ice bath under an atmosphereof nitrogen, is added dropwise a solution of 11.25 ml (98% reagent,54.45 mmol) of triethyl phosphonoacetate in 30 ml of THF. The resultingmixture is stirred in the ice bath for an additional 20 minutes and asolution ofN-methyl-N-phenethyl-2-[(5-benzyloxy-3-formyl)indol-1-yl]acetamide (15.5g, 36.3 mmol)in 80 ml of THF is added quickly. The ice bath is thenremoved and the mixture stirred for 18 hours at room temperature.

The reaction is quenched with water and ethyl acetate is added. Thelayers are separated and the organic layer is washed with brine, driedover MgSO₄ and concentrated in vacuo to give a beige oil. The crudeproduct is purified by dry column chromatography over silica gel elutingwith a solvent system of 10% ethyl acetate in methylene chloride to giveN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamide.Trituration of this substance in diethyl ether gives pure compound as awhite powder (m.p. 136°-139° C. (dec)).

Example 23N-methyl-N-phenethyl-2[-5-benzyloxy-3-(2-carboxyvinyl)indol-1-yl]acetamide

To a suspension of 14.85 g (29.9 mmol) ofN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamidein 750 ml of ethanol is added a solution of 2.52 g of potassiumhydroxide in 40 ml of water. The resulting suspension is stirred in aheating bath of 50° C. for 20 hours and another batch of KOH solution(1.75 g of KOH in 40 ml of water) is added. The mixture is stirred at50° C. for seven days after which time a homogeneous solution isobtained.

After cooling to room temperature, ethanol is removed in vacuo. Theresidue is mixed with water and the unreacted ester extracted into ethylacetate. The pH of the aqueous layer is adjusted to about 7 with 1Naqueous HCl solution. The white precipitate obtained is collected byfiltration, washed with water and dried in vacuo to yieldN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxyvinyl)indol-1-yl]acetamideas a white powder (m.p. 190°-192° C. (dec)).

Example 24N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-(1-pyrrolidinecarbonyl)vinyl)indol-1-yl]acetamide

To a mixture of 0.63 g (1.34 mmol) ofN-methyl-N-phenethyl-2-(5-benzyloxy-3-(2-carboxyvinyl)indol-1-yl]-acetamidein 15 ml of methylene chloride, cooled to 0° C. with an external icebath, is added dropwise 0.26 ml (3.02 mmol) of oxalyl chloride, followedimmediately with 3 drops of N,N-dimethylformamide. The mixture isstirred in an ice bath for 30 minutes and then for 1 hour with thecooling bath removed. The reaction mixture is then concentrated invacuo. The residue obtained is dissolved in 10 ml of methylene chlorideand this solution is added dropwise to a mixture of 0.11 ml (1.34 mmol)of pyrrolidine, 0.24 ml of pyridine and 15 ml of methylene chloride withstirring at 0° C. (ice bath). The resulting reaction mixture is stirredat room temperature for several hours and quenched with saturatedaqueous NH₄ Cl solution. Ethyl acetate and water are added and thelayers separated. The organic layer is washed with 1N aqueous HClsolution and water, dried over magnesium sulfate and concentrated invacuo. The residue is triturated in hot ethyl acetate to giveN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-(1-pyrrolidinecarbonyl)-vinyl)indol-1-yl]acetamide(m.p. 185°-187° C.).

Example 25N-methyl-N-phenethyl-2[-5-benzyloxy-3-(2-carbethoxyethyl)indol-1-yl]acetamide

A mixture of 0.93 g ofN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamide,0.5 g of 10% palladium on activated carbon and 150 ml of ethanol isshaken under 40 psi of hydrogen on a Parr Apparatus for 40 minutes. Themixture is filtered to remove the catalysts and the filtrate isconcentrated in vacuo. The residue is purified by dry columnchromatography over silica gel eluting with a solvent system of ethylacetate/hexane (2:1, v/v) to giveN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyethyl)indol-1-yl]acetamideas white powder (m.p. 81°-83° C.).

Example 26N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxyethyl)indol-1-yl]acetamide

To a suspension of 0.7 g (1.4 mmol) ofN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyethyl)indol-1-yl]acetamidein 20 ml of ethanol is added a solution of 0.2 g of potassium hydroxidein 3 ml of water. The mixture is stirred at room temperature for 18hours and concentrated in vacuo. The residue is dissolved in water andthe resulting solution adjusted to pH 4 with 1N aqueous HCl solution.The precipitate which forms is extracted into ethyl acetate. The organicsolution is washed with brine, dried over magnesium sulfate andconcentrated in vacuo to giveN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxyethyl)indol-1-yl]acetamideas a beige powder (m.p. 122°-125° C.).

Example 27N-(4-methoxyphenethyl)-N-methyl-2-[(5-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamide

When N-methyl-N-phenethyl-2-[(5-benzyloxy-3-formyl)-indol-1-yl]acetamidein the procedure of Example 22 is replaced withN-(4-methoxy)phenethyl-N-methyl-2-[(5-benzyloxy-3-formyl)indol-1-yl]acetamidethen the product prepared isN-(4-methoxyphenethyl)-N-methyl-2-[(5-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamide. NMR confirms this structure.

Example 28

N-methyl-N-phenethyl-2-6-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamide

WhenN-methyl-N-phenethyl-2-[(5-benzyloxy-3-formyl)-indol-1-yl)]acetamide inthe procedure of Example 22 is replaced with N-methyl-N-phenethyl-2-[(6-benzyloxy-3-formyl)indol-1-yl]acetamide then theproduct prepared isN-methyl-N-phenethyl-2-[6-benzyloxy-3-(2-carbethoxyvinyl)-indol-1-yl]acetamide.NMR confirms this structure.

Example 29 N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carbethoxyvinylindol-1-yl]acetamide

When N-methyl-N-phenethyl-2-[(5-benzyloxy-3-formyl)-indol-1-yl]acetamidein the procedure of Example 22 is replaced withN-methyl-N-phenethyl-2-[(4-benzyloxy-3-formyl)indol-1-yl]acetamide thenthe product prepared isN-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carbethoxyvinyl)-indol-1-yl]acetamide.(m.p. 110°-120° C.)

Example 30 N-methyl-N-phenethyl-2-[7-benzyloxy-3-(2-carbethoxyvinylindol-1-yl]acetamide

When N-methyl-N-phenethyl-2-[(5-benzyloxy-3-formyl)indol-1-yl]acetamidein the procedure of Example 22 is replaced withN-methyl-N-phenethyl-2-[(7-benzyloxy-3-formyl)indol-1-yl]acetamide thenthe product prepared isN-methyl-N-phenethyl-2-[7-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamide.NMR confirms this structure.

Example 31N-methyl-N-phenethyl-2-[3-(2-carbethoxyvinyl)-5-(2-(N-methyl-N-phenethyl)amino-2-oxo)ethoxyindole-1-yl]acetamide

When N-methyl-N-phenethyl-2-[(5-benzyloxy-3-formyl)indol-1-yl]acetamidein the procedure of Example 22 is replaced withN-methyl-N-phenethyl-2-[(5-(2-methylphenethylamino-2-oxo)ethoxy-3-formyl)indol-1-yl]acetamide then the product prepared isN-methyl-N-phenethyl-2-[3-(2-carbethoxyvinyl)-5-(2-(N-methyl-N-phenethyl)amino-2-oxo)ethoxyindol-1-yl]acetamide. NMRconfirms this structure.

Example 32N-methyl-N-phenethyl-2-3-(2-carbethoxyvinyl)-5-(4-methylbenzyloxyl)indol-1-yl]acetamide

When N-methyl-N-phenethyl-2-[(5-benzyloxy-3-formyl)indol-1-yl]acetamidein the procedure of Example 22 is replaced withN-methyl-N-phenethyl-2-[(5-(4-methylbenzyloxy)-3-formyl)indol-1-yl]acetamidethen the product prepared isN-methyl-N-phenethyl-2-[3-(2-carbethoxyvinyl)-5-(4-methylbenzyloxy)indol-1-yl]acetamide.NMR confirms this structure.

Example 331-benzyl-3-(2-carbethoxyvinyl)-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole

When N-methyl-N-phenethyl-2-[(5-benzyloxy-3-formyl)indol-1-yl]acetamidein the procedure of Example 22 is replaced with1-benzyl-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole-3-carboxaldehydethen the product prepared is1-benzyl-3-(2-carbethoxyvinyl)-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole.NMR confirms this structure.

Example 34

When triethylphosphonoacetate in the procedure of Example 22 is replacedwith the phosphonates of Table I below andN-methyl-N-phenethyl-2-[(5-benzyloxy-3-formyl)indol-1-yl]acetamide isreplaced by the various aldehydes and ketones of this invention then thecorresponding product is prepared. A representative list of compounds soprepared may be found in Examples 35-41 of Table II below.

TABLE I

trimethylphosphonoacetate

triethylphosphonoacetate

tripropylposphonoacetate

tributylphosphonoacetate

tri-tert-butylphosphonoacetate

triethylphosphono-2-propionate

triethylphosphono-3-butanoate

triethylphosphono-2-buten-2-oate

triethylphosphono-4-buten-2-oate

TABLE II Example 35N-methyl-N-phenethyl-2[-5-benzyloxy-3-(2-carb-t-butoxyvinyl)indol-1-yl]acetamide

(Solvent system ethylacetate/hexane; m.p. 135° C. (dec.).)

Example 36N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbmethoxyvinyl)indol-1-yl]acetamide

NMR confirms this structure. (m.p. 155°-156° C.)

Example 37N-methyl-N-phenethyl-2-[2-methyl-4-benzyloxy-3-(2-carbethoxy-2-methylvinyl)indol-1-yl]acetamideExample 38N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxy-2-ethylvinyl)indol-1-yl]acetamide

(m.p. 130°-131° C. (dec.))

Example 39N-methyl-N-phenethyl-2-[1-benzyloxy-3-(2-carbethoxy-2-methylvinyl)indol-5-yl]acetamideExample 40N-methyl-N-phenethyl-2-[4-benzyloxy-3-(4-carbethoxy-2-ethylvinyl)indol-1-yl]acetamideExample 41N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxy-1,3-butadienyl)indol-1-yl]acetamide

NMR confirms this structure.

Example 42N-(4-methoxyphenethyl)-N-methyl-2[-(5-benzyloxy-3-(2-carboxyvinyl)indol-1-yl]acetamide

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxy-vinyl)indol-1-yl]acetamidein the procedure of Example 23 is replaced withN-(4-methoxyphenethyl)-N-methyl-2-[(5-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamidethen the product prepared isN-(4-methoxyphenethyl)-N-methyl-2-[(5-benzyloxy-3-(2-carboxyvinyl)indol-1-yl]acetamide.(m.p. 161°-162° C. (dec.))

Example 43N-methyl-N-phenethyl-2-[6-benzyloxy-3-(2-carboxyvinyl)indol-1-yl]acetamide

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxy-vinyl)indol-1-yl]acetamidein the procedure of Example 23 is replaced withN-methyl-N-phenethyl-2-[6-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamidethen the product prepared isN-methyl-N-phenethyl-2-[6-benzyloxy-3-(2-carboxyvinyl)indol-1-yl]acetamide.(m.p. 201°-202° C. (dec.))

Example 44N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carboxyvinyl)indol-1-yl]acetamide

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamidein the procedure of Example 23 is replaced withN-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamidethen the product prepared isN-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carboxyvinyl)-indol-1-yl]acetamide.(m.p. 173°-175° C. (dec.))

Example 45N-methyl-N-phenethyl-2-[7-benzyloxy-3-(2-carboxyvinyl)indol-1-yl]acetamide

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamidein the procedure of Example 23 is replaced withN-methyl-N-phenethyl-2-[7-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamidethen the product prepared isN-methyl-N-phenethyl-2-[7-benzyloxy-3-(2-carboxyvinyl)-indol-1-yl]acetamide.(m.p. 192°-193° C. (dec.))

Example 46N-methyl-N-phenethyl-2-[3-(2-carboxyvinyl)-5-(2-(N-methyl-N-phenethyl)amino-2-oxo)ethoxyindol-1-yl]acetamide

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamidein the procedure of Example 23 is replaced withN-methyl-N-phenethyl-2-[3-(2-carbethoxyvinyl)-5-(2-(N-methyl-N-phenethyl)amino-2-oxo)ethoxyindol-1-yl]acetamide then the product prepared isN-methyl-N-phenethyl-2-[3-(2-carboxyvinyl)-5-(2-(N-methyl-N-phenethyl)amino-2-oxo)-ethoxyindol-1-yl]acetamide.(m.p. 94°-96° C. (dec.))

Example 47N-methyl-N-phenethyl-2-[3-(2-carboxyvinyl)-5-(4-methylbenzyloxy)indol-1-yl]acetamide

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamidein the procedure of Example 23 is replaced withN-methyl-N-phenethyl-2-[3-(2-carbethoxyvinyl)-5-(4-methylbenzyloxy)indol-1-yl]acetamidethen the product prepared isN-methyl-N-phenethyl-2-[3-(2-carboxyvinyl)-5-(4-methylbenzyloxy)indol-1-yl]acetamide.(m.p. 164°-166° C.)

Example 48N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxy-2-methylvinyl)indol-1-yl]acetamideN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2(Z)-carboxy-2-methylvinyl)indol-1-yl]acetamide

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamidein the procedure of Example 23 is replaced withN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxy-2-methylvinyl)indol-1-yl]acetamidethen the product prepared isN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxy-2-methylvinyl)-5-(4-methoxybenzyloxy)indol-1-yl]acetamide.(m.p. 220°-231° C. (dec.))

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamidein the procedure of Example 23 is replaced withN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-(Z)-carbethoxyvinyl)indol-1-yl]acetamide,then the product prepared isN-metyl-N-phenethyl-2-[5-benzyloxy-3-(Z)-2-carboxy-2-methylvinyl)indol-1-yl]acetamideas a white powder. (m.p. 155°-160° C.)

Example 49N-methyl-N-phenethyl-2-[5-benzyloxy-3-(4-carboxy-1,3-butadienyl)indol-1-yl]acetamide

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamidein the procedure of Example 23 is replaced withN-methyl-N-phenethyl-2-[1-benzyloxy-3-(2-carbethoxy-2-methylvinyl)indol-5-yl]acetamidethen the product prepared isN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxy-1,3-butadienyl)indol-1-yl]acetamide.(solvent system (acetone/ether) m.p. 189°-190° C.)

Example 501-benzyl-3-(2-carboxyvinyl)-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamidein the procedure of Example 23 is replaced with1-benzyl-3-(2-carbethoxyvinyl)-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindolethen the product prepared is1-benzyl-3-(2-carboxyvinyl)-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole.(m.p. 96°-99° C.)

Example 51N-methyl-N-phenethyl-2-[2-methyl-4-benzyloxy-3-(2-carboxy-2-methylvinyl)indol-1-yl]acetamide

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamidein the procedure of Example 23 is replaced withN-methyl-N-phenethyl-2-[2-methyl-4-benzyloxy-3-(2-carbethoxy-2-methylvinyl)indol-1-yl]acetamidethen the product prepared isN-methyl-N-phenethyl-2-[2-methyl-4-benzyloxy-3-(2-carboxy-2-methylvinyl)indol-1-yl]acetamide.

Example 52N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxy-2-ethylvinyl)indol-1-yl]acetamide

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamidein the procedure of Example 23 is replaced withN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxy-2-ethylvinyl)indol-1-yl]acetamidethen the product prepared isN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxy-2-ethylvinyl)indol-1-yl]acetamide.(m.p. 205°-207° C.)

Example 53

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyvinyl)indol1-yl]acetamidein the procedure of Example 25 is replaced by the unsaturated esters ofExamples 27-33 and 35-41 then the products prepared are shown in TableIII below.

TABLE III

N-(4-methoxyphenethyl)-N-methyl-2-[(5-benzyloxy-3-(2-carbethoxyethyl)indol1-yl]acetamide

N-methyl-N-phenethyl-2-[6-benzyloxy-3-(2-carbethoxyethyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carbethoxyethyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[7-benzyloxy-3-(2-carbethoxyethyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[3-(2-carbethoxyethyl)-5-(2-(N-methyl-N-phenethyl)amino-2-oxo)ethoxyindol-1-yl]acetamide

N-methyl-N-phenethyl-2-[3-(2-carbethoxyethyl)-5-(4-methylbenzyloxy)indol-1-yl]acetamide

1-benzyl-3-(2-carbethoxyethyl)-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carb-t-butoxyethyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbmethoxyethyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[2-methyl-4-benzyloxy-3-(2-carbethoxypropyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxybutyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[1-benzyl-3-(2-carbethoxypropyl)indol-5-yl]acetamide

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxypropyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(4-carbethoxybutyl)indol-1-yl]acetamide

Example 54

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyethyl)indol-1-yl]acetamidein the procedure of Example 26 is replaced by the compound of Table IIIthen the products prepared are shown in Table IV below.

TABLE IV

N-(4-methoxyphenethyl)-N-methyl-2-[(5-benzyloxy-3-(2-carboxyethyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[6-benzyloxy-3-(2-carboxyethyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carboxyethyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[7-benzyloxy-3-(2-carboxyethyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[3-(2-carboxyethyl)-5-(2-(N-methyl-N-phenethyl)amino-2-oxo)ethoxyindol-1-yl]acetamide

N-methyl-N-phenethyl-2-[3-(2-carboxyethyl)-5-(4-methylbenzyloxy)indol-1-yl]acetamide

1-benzyl-3-(2-carboxyethyl)-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxyethyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxyethyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[2-methyl-4-benzyloxy-3-(2-carboxypropyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[5-benzyoxy-3-(2-carboxybutyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[1-benzyl-3-(2-carboxypropyl)indol-5-yl]acetamide

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxypropyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(4-carboxybutyl)indol-1-yl]acetamide

Example 55N-methyl-N-phenethyl-2-[5-benzyloxy-3-2-cyanovinyl)indol-1-yl]acetamide

To a suspension of 2 g (8.30 mmoles) of acetonitriletriphenylphosphoniumbromide (prepared from 1.24 g bromo-acetonitrile and 2.98 gtriphenylphosphine refluxed in toluene for 1 hour) in 100 ml ofdimethylformamide is added 0.27 g (9.13 mmoles) of an 80% sodium hydridein oil dispersion. After stirring at 0° C. for 1 hour, 3.54 g (8.30mmoles) ofN-methyl-N-phenethyl-2-[(5-benzyloxy-3-formyl)indol-1-yl]acetamide in 20ml of dimethylformamide is added and stirred for 2 hours. The mixture ispoured into ice water, extracted with ethyl acetate which is dried andconcentrated in vacuo. Purification by flash column chromatographythrough silica gel givesN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-cyanovinyl)indol-1-yl]acetamide.

Example 56N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-yl)vinylindol-1-yl]acetamide

A suspension of 0.94 g (2 mmoles) ofN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-cyanovinyl)indol-1-yl]acetamide,0.56 g (10.45 mmoles)of ammonium chloride and 0.68 g (10.45 mmoles) ofsodium azide in 20 ml of dimethyl-formamide is heated at 100° C. for 18hours. The mixture is poured into ice water. Addition of ethyl acetategives a precipitate which is collected and triturated in acetone to giveN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-yl)vinylindol-1-yl]acetamide.(m.p. 203°-205° C.)

Example 57N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-2-tetrazol-5-yl)ethylindol-1-yl]acetamide

To a solution 0.2 g (0.42 mmoles) ofN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-ylvinyl)indol-1-yl]acetamidein 30 ml of ethanol is added 0.08 g of 10% palladium on carbon and themixture is shaken under 30 psi of hydrogen for 4 hours. The mixture isfiltered and the filtrate concentrated in vacuo. The residue iscrystallized from methylene chloride to giveN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-yl)ethylindol-1-yl]acetamide.

Example 58

When bromoacetonitrile in the procedure of Example 55 is replaced withthe reagents of Table V below then the corresponding products areprepared which are further convened to the corresponding tetrazoles byExamples 56 and 57.

TABLE V

bromoacetonitrile

3-bromopropanenitrile

2-bromopropanenitrile

2-bromobutanenitrile

3-bromobutanenitrile

2-methyl-3-bromopropanenitrile

4-bromo-2-butenenitrile

4-bromo-2-pentenenitrile

Example 59

When N-methyl-N-phenethyl-2-[(5-benzyloxy-3-formyl)indol-1-yl]acetamideis replaced in Example 55 and 58 with the aldehydes and ketones of thisinvention the corresponding tetrazoles are prepared. A representativelist of products so prepared is shown in Table VI.

TABLE VI

N-(4-methoxyphenethyl)-N-methyl-2-[(5-benzyloxy-3-(2-tetrazol-5-yl)vinylindol-1-yl]acetamide

N-methyl-N-phenethyl-2-[6-benzyloxy-3-(2-tetrazol-5-yl)vinylindol-1-yl]acetamide

N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-tetrazol-5-yl)vinylindol-1-yl]acetamide

N-methyl-N-phenethyl-2-[7-benzyloxy-3-(2-tetrazol-5-yl)vinylindol-1-yl]acetamide

N-methyl-N-phenethyl-2-[3-(2-tetrazol-5-yl)vinyl-5-(2-(N-methyl-N-phenethyl)amino-2-oxo)ethoxyindol-1-yl]acetamide

N-methyl-N-phenethyl-2-[3-(2-tetrazol-5-yl)vinyl-5-(4-methylbenzyloxy)indol-1-yl]acetamide

1-benzyl-3-(2-tetrazol-5-yl)vinyl-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-yl)vinylindol-1-yl]acetamide

N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-tetrazol-5-yl-2-methylvinyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-yl-2-ethylvinyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[1-benzyl-3-(2-tetrazol-5-yl-2-methylvinyl)indol-5-yl]acetamide

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-yl-2-methylvinyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(4-tetrazol-5-yl-1,3-butadienyl)indol-1-yl]acetamide

N-(4-methoxyphenethyl)-N-methyl-2-[5-benzyloxy-3-(2-tetrazol-5-ylethyl)indol-1-yl]acetamide

N-(4-methoxyphenethyl)-N-methyl-2-[4-benzyloxy-3-(2-tetrazol-5-ylethyl)indol-1-yl]acetamide

N-(4-methoxyphenethyl)-N-methyl-2-[7-benzyloxy-3-(2-tetrazol-5-ylethyl)indol-1-yl]acetamide

N-(4-methoxyphenethyl)-N-methyl-2-[5-(2-(N-methyl-N-phenethyl)amino-2oxo)-3-(2-tetrazol-5-ylvinyl)ethoxy-indol-1-yl]-acetamide

N-(4-methoxyphenethyl)-N-methyl-2-[5-(4-methylbenzyloxy)-3-(2-tetrazol-5-ylvinyl)indol-1-yl]acetamide

1-benzyl-3-(2-tetrazol-5-ylethyl)-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-yl)ethylindol-1-yl]acetamide

N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-tetrazol-5-ylpropyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-ylbutyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[1-benzyl-3-(2-tetrazol-5-ylpropyl)indol-5-yl]acetamide

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-ylpropyl)indol-1-yl]acetamide

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(4-tetrazol-5-yl)butylindol-1-yl]acetamide

Example 60N-methyl-N-phenethyl-2-[5-benzyloxy-3-(4-carboxy-3-methyl-3-butenyl)indol-1-yl]acetamide

Step A:N-methyl-N-phenethyl-2[-3-(2-acetyl)vinyl-5-benzyloxyindol-1-yl]acetamide

A mixture 2 g (4.68 mmol) ofN-methyl-N-phenethyl-2-[3-benzyloxy-2-formylindol-1-yl]acetamide, 125 mlof acetone and 25 ml of 1N aqueous sodium hydroxide solution is stirredat room temperature for 72 hours. The mixture is then concentrated invacuo. The pH of the concentrated mixture is adjusted to about 6 with 1Naqueous HCl solution. Ethyl acetate is added and the layers separated.The organic layer is washed with brine, dried over magnesium sulfate andconcentrated in vacuo. The yellow foamy residue is triturated inether/acetone to giveN-methyl-N-phenethyl-2-[3-(2-acetyl)vinyl-5-benzyloxyindol-1-yl]acetamide.(m.p. 150°-152° C.)

Step B:N-methyl-N-phenethyl-2-[3-(2-acetylethyl-5-benzyloxyindol-1-yl]acetamide

When the procedure of Example 25 is followed,N-methyl-N-phenethyl-2-[3-(2-acetyl)vinyl-5-benzyloxyindol-1-yl]acetamideis hydrogenated toN-methyl-N-phenethyl-2-[3-(2-acetylethyl)-5-benzyloxyindol-1-yl]acetamide.(m.p. 120-121° C.)

Step C:N-methyl-N-phenethyl-2-[5-benzyloxy-3-(4-carbethoxy-3-methyl-3-butenyl)indol-1-yl]acetamide

When the procedure of Example 22 is followed,N-methyl-N-phenethyl-2-[3-acetylethyl-5-benzyloxyindol-1-yl]acetamide isreacted with triethylphosphonoacetate to giveN-methyl-N-phenethyl-2-[5-benzyloxy-3-(4-carbethoxy-3-methyl-3-butenyl)indol-1-yl]acetamideas a yellow oil which is NMR verified.

Step D:N-methyl-N-phenethyl-2[-5-benzyloxy-3-(4-carboxy-3-methyl-3-butenyl)indol-1yl]acetamide

When the procedure of Example 26 is followed,N-methyl-N-phenethyl-2-[5-benzyloxy-3-(4-carbethoxy-3-methyl-3-butenyl)indol-1-yl]acetamideis hydrolyzed to giveN-methyl-N-phenethyl-2-[5-benzyloxy-3-(4-carboxy-3-methyl-3-butenyl)indol-1-yl]acetamideas a yellow foamy substance. NMR confirms this structure.

Example 61N-methyl-N-phenethyl-2-(5-benzyloxy-2-carboxyindol-1-yl)acetamideN-methyl-N-phenethyl-2-(5-benzyloxy-3-carboxyindol-1-yl)acetamide

Step A:N-methyl-N-phenethyl-2-(5-benzyloxy-2-carbomethoxyindol-1-yl)acetamide

Following the procedure of Example 10, 5-benzyloxy-2-carbomethoxyindoleis alkylated with N-methyl-N-phenethyl-2-bromoacetamide to giveN-methyl-N-phenethyl-2-(5-benzyloxy-2-carbomethoxyindol-1-yl)acetamide.(m.p. 155°-156° C.)

Step B:N-methyl-N-phenethyl-2-(5-benzyloxy-2-carboxyindol-1-yl)acetamide

Following the procedure of Example 23 the ester of Step A is hydrolyzedto giveN-methyl-N-phenethyl-2-(5-benzyloxy-2-carboxyindol-1-yl)acetamide. (m.p.250° C. (dec.))

Step C:N-methyl-N-phenethyl-2-(5-benzyloxy-3-carboxyindol-1-yl)acetamide

When 5-benzyloxy-3-carbomethoxyindol is used in Step A and the alkylatedproduct obtained is then hydrolyzed according to Step B,N-methyl-N-phenethyl-2-(5-benzyloxy-3-carboxyindol-1-yl]acetamide isprepared. (m.p. 182°-185° C.)

Example 62N-methyl-N-phenethyl-2-[5-benzyloxy-1-(2-carboxyvinyl)indol-3-yl]acetamide

Step A: N-methyl-N-phenethyl-2-(5-benzyloxyindol-3-yl)acetamide

When the procedure of Example 14 is followed, 5-benzyloxyindole-3-aceticacid and N-methyl-N-phenethylamine are reacted to giveN-methyl-N-phenethyl-2-(5-benzyloxyindol-3-yl)acetamide. (m.p. 146° C.(dec.))

Step B:N-methyl-N-phenethyl-2-[5-benzyloxy-1-(2-carbethoxyvinyl)indol-3-yl]acetamide

To a mixture of 1.579 g (3.96 mmol) ofN-methyl-N-phenethyl-2-(5-benzyloxyindol-3-yl)acetamide and 0.4 ml ofbenzyltrimethylammonium hydroxide (40% solution in methanol) in 15 ml ofdioxane is added with stirring 0.44 ml (0.43 g, 4.35 mmol) of ethylpropriolate. A reddish solution is obtained, which is stirred at roomtemperature for 18 hours and concentrated in vacuo. The residue is takenup in ethyl acetate, washed with brine, dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by dry columnchromatography over silica gel eluting with a solvent system of 5% ethylacetate in methylene chloride to yield 450 mg ofN-methyl-N-phenethyl-2-[5-benzyloxy-1-(2-carbethoxyvinyl)indol-3-yl]acetamide.

Step C:N-methyl-N-phenethyl-2-[5-benzyloxy-1-(2-carboxyvinyl)indol-3yl]acetamide

Following the procedure of Example 23 the ester of Step B is hydrolyzedtoN-methyl-N-phenethyl-2-[5-benzyloxy-1-(2-carboxyvinyl)indol-3-yl]acetamide.(m.p. 104°-108° C. (dec.))

Example 63

When pyrrolidine in the procedure of Example 24 is replaced with asuitable amine andN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxyvinyl)-indol-1-yl]acetamideis replaced by the acids prepared by the above examples, then thecorresponding amide is prepared.

Example 64 N-benzyl-5-benzyloxy-3-(2-tetrazol-5-ylethyl)indole

Step A: N-benzyl-5-benzyloxy-3-formylindole

Following the procedure of Example 10, benzyl bromide is used in placeof N-methyl-N-phenethyl-2-bromoacetamide to giveN-benzyl-5-benzyloxy-3-formylindole.

Step B: N-benzyl-5-benzyloxy-3-(2-cvanovinyl)indole

Following the procedure of Example 55,N-benzyl-5-benzyloxy-3-formylindole is treated with acetonitriletriphenylphosphonium bromide to giveN-benzyl-5-benzyloxy-3-(2-cyanovinyl)indole.

Step C: N-benzyl-5-benzyloxy-3-(2tetrazol-5-ylvinyl)indole

Following the procedure of Example 56,N-benzyl-5-benzyloxy-3-(2-cyanovinyl)indole is reacted with the sodiumazide to give N-benzyl-5-benzyloxy-3-(2-tetrazol-5-ylvinyl)indole. (m.p.178°-180° C. (dec.))

Step D: N-benzyl-5-benzyloxy-3-(2-tetrazol-5-ylethyl)indole

Following the procedure of Example 57,N-benzyl-5-benzyloxy-3-(2-tetrazol-5-ylvinyl)indole is reduced to giveN-benzyl-5-benzyloxy-3-(2-tetrazol-5-ylethyl)indole.

Example 65N-methyl-N-phenethyl-2-[(5benzyloxy-3-dimethylamidomethyl)indol-1-yl]acetamide

Step A:N-methyl-N-phenethyl-2-[(5-benzyloxy-3-carbomethoxymethyl)indol-1-yl]acetamide

Following the procedure of Example 10 and using5-benzyloxy-3-carbomethoxymethylindole in place of5-benzyloxyindole-3-carboxaldehyde the product prepared isN-methyl-N-phenethyl-2-[(5-benzyloxy-3-carbomethoxymethyl)indol-1-yl]acetamide.

Step B:N-methyl-N-phenethyl-2-[(5-benzyloxy-3-carboxymethyl)indol-1-yl]acetamide

Following the procedure of Example 26,N-methyl-N-phenethyl-2-[(5-benzyloxy-3-carbomethoxymethyl)indol-1-yl]acetamideis hydrolyzed to giveN-methyl-N-phenethyl-2-[(5-benzyloxy-3-carboxymethyl)indol-1-yl]acetamide.

Step C:N-methyl-N-phenethyl-2-[(5-benzyloxy-3-dimethylamidomethyl)indol-1-yl]acetamide

Following the procedure of Example 24, the acid from Step B is convertedto the acid halide and treated with dimethylamine to obtainN-methyl-N-phenethyl-2-[(5-benzyloxy-3-dimethylamidomethyl)indol-1-yl]acetamide.

Example 66N-methyl-N-phenethyl-2-[(5-(2-methylphenethylamino-2-oxo)ethoxy-3-diethylamidomethyl)indol-1-yl]acetamide

Step A:N-methyl-N-phenethyl-2-[(5-(2-methylphenethylamino-2-oxo)ethoxy-3-carbomethoxymethyl)indol-1-yl]acetamide

Following the procedure of Example 10,5-benzyloxyindole-3-carboxaldehyde is replaced with5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxy-3-carbomethoxy-methylindoleto obtainN-methyl-N-phenethyl-2-[(5-(2-methylphenethylamino-2-oxo)ethoxy-3-carbomethoxymethyl)indol-1-yl]acetamide.

Step B:N-methyl-N-phenethyl-2-[(5-(2-methylphenethylamino-2-oxo)ethoxy-3-carboxymethyl)indol-1-yl]acetamide

Following the procedure of Example 26, the ester from Step A ishydrolyzed to giveN-methyl-N-phenethyl-2-[(5-(2-methylphenethylamino-2-oxo)ethoxy-3-carboxymethyl)indol-1-yl]acetamide.

Step C:N-methyl-N-phenethyl-2-[(5-(2-methylphenethyl-amino-2-oxo)ethoxy-3-diethylamidomethyl)indol-1-yl]acetamide

Following the procedure of Example 24 the acid from Step B is convenedto the acid halide and treated with diethylamine to obtainN-methyl-N-phenethyl-2-[(5-(2-methylphenethylamino-2-oxo)ethoxy-3-diethylamidomethyl)indol-1-yl]acetamide.

Example 671-benzyl-3-carboxymethyl-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole

Step A:3-carbomethoxymethyl-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole

Following the procedure of Example 2, 5-hydroxyindole is replaced by3-carbomethoxymethyl-5-hydroxyindole to obtain3-carbomethoxymethyl-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole.

Step B:1-benzyl-3-carbomethoxymethyl-5-[2-(N-methyl-N-phenethyl)-amino-2-oxolethoxyindole

Following the procedure of Example 10 and reacting benzyl bromide with3-carbomethoxymethyl-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindolethe product prepared is1-benzyl-3-carbomethoxymethyl-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole.

Step C:1-benzyl-3-carboxymethyl-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole

Following the procedure of Example 26 the ester from Step B ishydrolyzed to give1-benzyl-3-carboxymethyl-5-[2-(N-methyl-N-phenethyl)amino-2-oxo]ethoxyindole.

Example 68N-methyl-N-phenethyl-2-[(4-benzyloxy-3-carboxy)indol-1-yl]acetamide

When 5-hydroxyindole in the procedure of Example 3 is replaced with3-carbethoxy-4-hydroxyindole and the resulting3-carbethoxy-4-benzyloxyindole is used in place of5-benzyloxyindole-3-carboxaldehyde in the procedure of Example 10, thenthe product obtained isN-methyl-N-phenethyl-2-[(4-benzyloxy-3-carbethoxy)indol-1-yl]acetamide.When the latter is used in place ofN-methyl-N-phenethyl-2-[(5-benzyloxy-3-formyl)indol-1-yl]acetamide thenthe product obtained isN-methyl-N-phenethyl-2-[(4-benzyloxy-3-carboxy)indol-1-yl]acetamide.(m.p. 120°-125° C.)

Example 69N-methyl-N-phenethyl-2-(4-benzyloxy-3-(2-trans-carboxy-2-methyl)vinylindol-1-yl)acetamide

Step A: N-methyl-N-phenethyl-2-(4-benzyloxy-3-formylindol-1-yl acetamide

To a suspension of sodium hydride (1.31 g, 80% suspension in mineraloil, 43.8 mM) in 65 ml of tetrahydrofuran (THF), cooled in an ice bath,is added dropwise a solution of 4-benzyloxyindole-3-carboxaldehyde (10.2g, 39.8 mM) in 55 ml of THF. The mixture is stirred in the cooling bathfor an additional 30 minutes; N-methyl-N-phenethyl-2-bromoacetamide(15.3 g, 59.7 mM) is then added. The resulting mixture is stirred atroom temperature for 18 hours. Ethyl acetate and 50% brine is added andthe layers are separated. The organic layer is washed with brine, driedover magnesium sulfate and concentrated in vacuo to give crude productas a beige oil. Purification on preparative HPLC (silica gel column, 20%ethyl acetate in methylene chloride) givesN-methyl-N-phenethyl-2-(4-benzyloxy-3-formylindol-1-yl)acetamide. (m.p.120°-122° C.)

Step B:N-methyl-N-phenethyl-2-(4-benzyloxy-3-(2-trans-carbethoxy-2-methyl)vinylindol-1-yl)acetamide

To a suspension of sodium hydride (0.259 g, 80% suspension in mineraloil, 8.64 mM) in 20 ml of THF, cooled in an ice bath, is added dropwise1.87 g (7.85 mM) of triethyl 2-phosphonopropionate. The clear solutionobtained in the reacting flask is stirred in the ice bath for anadditional 10 minutes and a solution ofN-methyl-N-phenethyl-2-(4-benzyloxy-3-formylindol-1-yl)acetamide (1.34g, 3.14 mM) in 20 ml of THF added quickly. The cooling bath is removedand the reaction mixture stirred at room temperature for 18 hours. Afterquenching the reaction with a small amount of water, ethyl acetate andbrine are added and the layers separated. The organic layer is washedwith brine, dried (MgSO₄), and concentrated in vacuo to give a crudemixture as a brown oil. This material is purified by hplc on a silicagel column, using a one-to-one mixture of ethyl acetate and hexane asthe solvent system, to give 0.89 g of the pure N-methyl-N-phenethyl-2-(4-benzyloxy-3-(2-trans-carbethoxy-2-methylvinyl)indol-1-yl)acetamide.Also obtained from this hplc separation is 0.48 g of the cis-isomer and0.05 g of a mixture of the cis and trans isomers confirmed by NMR.

Step C:N-methyl-N-phenethyl-2-(4-benzyloxy-3-(2-trans-carboxy-2-methyl)vinylindol-1-yl)acetamide

To a solution ofN-methyl-N-phenethyl-2-(4-benzyloxy-3-(2-trans-carbethoxy-2-methyl)vinylindol-1-yl)acetamide(0.7 g, 1.37 mM)in 0.3 ml of ethanol is added a solution of potassiumhydroxide (0.261 g, 4.12 mM) in 7 ml of water. The resulting mixture isheated in an oil bath of 50° C. for four days. After cooling to roomtemperature, the bulk of ethanol is removed in vacuo. The concentratedmixture is dissolved in water and extracted with diethyl ether. Theaqueous layer is acidified with 1N HCl to pH 6.5-7. The precipitateformed is extracted into ethyl acetate. The organic solution is washedwith brine, dried (MgSO₄) and concentrated in vacuo) to giveN-methyl-N-phenethyl-2-(4-benzyloxy-3-(2-trans-carboxy-2-methyl)vinylindol-1-yl) acetamide. (m.p. 199°-201°C.).

Example 70N-methyl-N-phenethyl-2-5-benzoylamide-3-(2-carboxyethyl)indol-1-yl]acetamide

Step A:N-methyl-N-phenethyl-2-(5-nitro-3-carboxaldehydeindol-1-yl)acetamide

To a mixture of sodium hydride (1.9 g, 78.9 mmol) in anhydroustetrahydrofuran (200 ml) at 0° C. is added portionwise5-nitro-3-carboxaldehydeindole (15.0 g, 78.9 mmol). The reaction isallowed to stir for 30 minutes. N-methyl-N-phenethyl-2-bromoacetamide(20.2 g, 78.9 mmol) is added and the reaction stirred for 16 hours andthen heated at reflux. After allowing to cool the solid is filtered off,the solvent is removed and the residue is crystallized fromchloroform/hexane to giveN-methyl-N-phenethyl-2-(5-nitro-3-carboxaldehydeindol-1-yl)acetamide.(m.p. 200° C.)

Step B:N-methyl-N-phenethyl-2-[5-nitro-3-(t-butyl-2-carboxyvinyl)indol-1-yl]acetamide

To a chilled solution of t-butyl diethylphosphono-acetate (5.4 g, 21.4mmol) in dimethylformamide (15 ml) sodium hydride (0.51 g, 21.4 mmol) isadded portionwise. The reaction is allowed to come to ambienttemperature and stirred for 1 hour. The aldehyde,N-methyl-N-phenethyl-2-(5-nitro-3-carboxaldehydeindol-1-yl)acetamide(5.2 g, 14.2 mmol) is added portionwise. After 11/2 hours the reactionis poured into water (600 ml) and extracted with ethyl acetate (3×10).The ethyl acetate layer is dried (Na₂ SO₄) and the solvent is removed.This gives a red oil which is crystallized for hexane/ethyl acetate togiveN-methyl-N-phenethyl-2-[5-nitro-3-(t-butyl-2-carboxyvinyl)indol-1-yl]acetamide.(m.p. 140°-143° C.)

Step C:N-methyl-N-phenethyl-2-[5-benzoylamide-3-t-butyl-2-carboxyethyl)indol-1-yl]acetamide

A mixture ofN-methyl-N-phenethyl-2-[5-nitro-3-(t-butyl-2-carboxyvinyl)indol-1-yl]acetamide(0.9 g, 1.9 mmol), tetrahydrofuran (30 ml), ethanol (30 ml), andpalladium on carbon (10%, 0.2 g) is shaken under hydrogen (45 psi).After 4 hours the mixture is filtered through celite and the solvent isremoved. The residue is added to a solution of N-benzoylimidazole (5.8mmol) in tetrahydrofuran (20 ml). After 16 hours the solvent is removedand methanol (50 ml) is added. The solution is allowed to stand for 11/2and the methanol is removed. The oil is chromatographed using silica geland an ethylacetate/hexane 1:1 solution until the methyl benzoate isremoved.

The solvent is changed to ethylacetate:hexane 2:1. This gives crudeproduct which is crystallized from CHCl₃ /ether/hexane to giveN-methyl-N-phenethyl-2-[5-benzoyl-amide-3-(t-butyl-2-carboxyethyl)indol-1-yl]acetamideas a white solid. (m.p. 158°-159° C.)

Step D:N-methyl-N-phenethyl-2-[5-1benzoylamide-3-(2-carboxyethyl)indol-1-yl]acetamide

A solution of (0.25 g, 0.46 mmol) ofN-methyl-N-phenethyl-2-[5-benzoyl-amide-3-(t-butyl-2-carboxyethyl)indol-1-yl]acetamideis dissolved in trifluoroacetic acid/methylene chloride (1:1, 6 ml).After stirring for 3 hours the solvent is removed and the residue isdissolved in a small amount of ethanol. Ethylether is added and thefluffy tan solid is filtered to giveN-methyl-N-phenethyl-2-[5-benzoylamide-3-(2-carboxyethyl)indol-1-yl]acetamide.(m.p. 9°-222° C.)

Example 711-[(N-methyl-N-(2-phenethyl)-2-acetamido]-6-benzyloxy-3-naphthoic acid

Step A: 3-carbomethoxy-4-(3methoxyphenyl)-3-butenoic acid

To a refluxing suspension of 15.71 g (140 mmol, 1.4 eq) of potassiumt-butoxide in 50 ml of t-butylalcohol is dropped in a mixture of 12.17(100 mmol) of 3-methoxybenzaldehyde and 15.70 ml (120 mmol, 1.2 eq) ofdimethyl succinate dissolved in 20 ml of t-butylalcohol. The mixture isrefluxed for 3 hours, concentrated in vacuo, acidified to pH ˜1 using 1NHCl, and extracted with ethylacetate. The organics are dried (MgSO₄) andconcentrated in vacuo to give3-carbomethoxy-4-(3-methoxyphenyl)-3-butenoic acid in the form of ayellow oil which is used directly in the next step.

Step B: 3-carbomethoxy-4-(3-methoxyphenyl)butanoic acid

A solution of 21.1 g (84 mmol) of3-carbomethoxy-4-(3-methoxyphenyl)-3-butenoic acid in 100 ml of aceticacid with 2.11 g of 10% Pd on carbon is shaken under H₂ atmosphere untilH₂ uptake ceases (approximately 4 hours). This is filtered throughcelite and the filtrate concentrated in vacuo several times from tolueneto afford 17.6 g of 3-carbomethoxy-4-(3-methoxyphenyl)butanoic acid inthe form of a yellow oil which is used directly in the next step.

Step C: 3-carbomethoxy-6-benzyloxy-1-tetralin

A solution of 14 g (55.57 mmol) of3-carbomethoxy-4-(3-methoxyphenyl)butanoic acid in 200 ml of CH₂ Cl₂ isrefluxed for 18 hours with 8.1 ml (110.99 mmol, 2 eq) of SOCl₂ and 2drops of DMF. After concentration in vacuo several times from CH₂ Cl₂,this is dissolved in 50 ml of 1,2-dichloroethane and dropped into asuspension of 22.19 g (166.49 mmol, 3 eq) of AlCl₃ in 200 ml of1,2-dichloro-ethane at 25° C. After refluxing for 3 hours, the cooledmixture is quenched with H₂ O, acidified to pH ˜1 using 1N HCl, andextracted with CH₂ Cl₂. The organics are dried (MgSO₄) and concentratedin vacuo. This is dissolved in 50 ml of DMF and heated at 60° C. for 18hours with 6 ml (47.68 mmol, 1.5 eq) of benzylbromide and 6.6 g (47.68mmol, 1.5 eq) of K₂ CO₃. The mixture is partitioned between ethylacetate and H₂ O. The organics are dried (MgSO₄) and concentrated invacuo. This is purified by flash silica gel chromatography using 20%ethyl acetate in hexanes as an eluent to give 3.0 g of3-carbomethoxy-6-benzyloxy-1-tetralin in the form of a pale yellowcrystalline solid. (m.p. 139°-140° C.)

Step D: 3-carbomethoxy-6-benzyloxy-1-naphthol

A solution of 3.4 g (10.96 mmol) of3-carbomethoxy-6-benzyloxy-1-tetralin and 3.5 g (10.96 mmol) ofpyridinium bromideperbromide in 30 ml of acetic acid is heated at 60° C.for 1 hour. The mixture is partitioned between Et₂ O and H₂ O. Theorganics are dried (MgSO₄) and concentrated in vacuo. The residue in 20ml of DMSO is stirred for 1 hour with 3.69 g (32.87 mmol, 3 eq) ofpotassium t-butoxide at 25° C. The mixture is acidified to pH 1 using 1NHCl, then partitioned between ethyl acetate and H₂ O . The organics aredried (MgSO₄) and concentrated in vacuo. To the residue in 25 ml of CH₂Cl₂ is added 1.95 g (12.05 mmol, 1.1 eq) of carbonyl diimidazole and acatalytic amount of DMAP which is stirred at 25° C. for 0.5 hours. Thisis then stirred for 18 hours with 2 ml of MeOH. This is concentrated invacuo and partitioned between ethyl acetate and 1N HCl. The organics aredried (MgSO₄) and concentrated in vacuo. This is purified by flashsilica gel chromatography using 15% ethyl acetate in hexanes as aneluent affords 0.50 g of 3-carbomethoxy- 6-benzyloxy-1-naphthol in theform of a white crystalline solid, (m.p. 179°-180° C.)

Step E:1-trifluoromethylsulfonyloxy-3-carbomethoxy-6-benzyloxynaphthalene

To 0.65 g (2.11 mmol) of 3-carbomethoxy-6-benzyloxy-1-naphthol in 20 mlof pyridine at 0° C. is added 0.43 ml (2.5 mmol, 1.2 eq) oftrifluoromethanesulfonic anhydride which is then stirred for 18 hours at25° C. The mixture is concentrated in vacuo and partitioned betweenethyl acetate and 1N HCl. The organics are dried (MgSO₄) andconcentrated in vacuo. Purification by flash silica gel chromatographyusing 7% ethyl acetate in hexanes as an eluent affords 0.5 g of1-trifluoromethylsulfonyloxy-3-carbomethoxy-6-benzyloxynaphthalene inthe form of a clear oil which is used directly in the next step.

Step F: 1-vinyl-3-carbomethoxy-6-benzyloxynaphthalene

A solution of 0.5 g (1.4 mmol) of1-trifluoromethylsulfonyloxy-3-carbomethoxy-6-benzyloxynaphthalene in 20ml of DMF is stirred at 25° C. for 18 hours with 0.18 g (4.27 mmol, 3eq) of LiCl, 0.46 ml (1.57 mmol, 1.1 eq) of vinyl-tributyltin and 0.019g (0.03 mmol, 0.02 eq) bis(triphenyl-phosphine) palladium (II) chloride.The mixture is partitioned between ethyl acetate and 1N HCl. Theorganics are dried (MgSO₄) and concentrated in vacuo. Purification byflash silica gel chromatography using 5% ethyl acetate in hexanes as aneluent affords 0.3 g of 1-vinyl-3-carbomethoxy-6-benzyloxynaphthalene inthe form of a yellow oil which is used directly in the next step.

Step G: 1-hydroxyethyl-3-carbomethoxy-6-benzyloxy-naphthalene

A solution of 0.3 g (0.9 mmol) of1-vinyl-3-carbomethoxy-6benzyloxynaphthalene and 0.9 ml (0.9 mmol) of1.0M BH₃.THF complex in 15 ml of THF is stirred at 25° C. for 2 hours.To this is added 1 ml of H₂ O, 1 ml of 1N NaOH and 1 ml of 30% H₂ O₂which is then stirred at 25° C. for 2 hours. The mixture is acidified topH ˜1 using 1N HCl and extracted with ethyl acetate. The organics aredried (MgSO₄) and concentrated in vacuo. Purification by flash silicagel chromatography using 15% ethyl acetate in hexanes as an eluentaffords 0.08 g of 1-hydroxyethyl-3-carbomethoxy-6-benzyloxynaphthalenein the form a yellow oil which is used directly in the next step.

Step H: 3-carbomethoxy-6-benzyloxy-1-naphthyl acetic acid

To a solution of 0.08 g (0.24 mmol) of1-hydroxyethyl-3-carbomethoxy-6-benzyloxynaphthalene in 10 ml of acetoneat 0° C. is added Jones reagent until a green precipitate forms. Afterstirring at 0° C. for 10 minutes, the mixture is partitioned betweenethyl acetate and H₂ O. The organics are dried (MgSO₄) and concentratedin vacuo to afford 0.081 g of 3-carbomethoxy-6-benzyloxy-1-naphthylacetic acid in the form of a light tan solid which is used directly inthe next step.

Step I:1-[(N-methyl-N-(2-phenethyl)-2-acetamido]-3-carbomethoxy-6-benzyloxynaphthalene

A solution of 0.051 g (0.23 mmol) of3-carbomethoxy-6-benzyloxy-1-naphthyl acetic acid, 0.041 g (0.25 mmol,1.1 eq) of carbonyl diimidazole and a catalytic amount of DMAP isstirred at 25° C. for 1 hour in 15 ml of CH₂ Cl₂. To this is added 0.037ml (0.25 mmol, 1.1 eq) of N-methyl-N-phenethylamine which is thenstirred at 25° C. for 18 hours. The mixture is concentrated in vacuo,then partitioned between ethyl acetate and 1N HCl. The organics aredried (MgSO₄) and concentrated in vacuo. Purification by thick layerprep plate chromatography developed in 10% acetone in hexanes affords0.1 g of1-[(N-methyl-N-(2-phenethyl)-2-acetamido]-3-carbomethoxy-6-benzyloxynaphthalenein the form of a yellow oil which is used directly in the next step.

Step J: 1-[(N-methyl-N-(2-phenethyl-2-acetamido]-6-benzyloxy-3-naphthoicacid

A solution of 0.07 g (0.15 mmol) of1-[(N-methyl-N-(2-phenethyl)-2-acetamido]-3-carbomethoxy-6-benzyloxynaphthaleneand 0.31 g (0.75 mmol, 5 eq) of lithium hydroxide monohydrate in 20 mlof a 1:1:1 mixture of THF:H₂ O:MEOH is stirred at 25° C. for 10 hours.The mixture is acidified to pH ˜1 using 1N HCl and extracted with ethylacetate. The organics are dried (MgSO₄) and concentrated in vacuo. Theresidue is triturated with ET₂ O/hexanes and the solid filtered off toafford 0.035 g of1-[(N-methyl-N-(2-phenethyl)-2-acetamido]-6-benzyloxy-3-naphthoic acidin the form of a white crystalline solid. (m.p. 76°-79° C.)

Example 72N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxy-2-methylvinyl)indol-1-yl]acetamideN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-(E)-carbethoxy-2-methylvinyl)indol-1-yl]acetamideN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-(Z)-carbethoxy-2-methylvinyl)indol-1-yl]acetamide

Following the procedure of Example 34,N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxy-2-methylvinyl)indol-1-yl]acetamideis prepared. (m.p. 128°-130° C.)

This substance is further purified on a silica gel flash column, elutingwith a solvent system of 2% ethyl acetate in methylene chloride to giveN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-(E)-carbethoxy-2-methylvinyl)-indol-1-yl]acetamideandN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-(Z)-carbethoxy-2-methylvinyl)indol-1-yl]acetamide.NMR confirms these structures.

Example 73N-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carboxy-2-ethylvinyl)indol-1-yl]acetamide

WhenN-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboethoxyvinyl)-indol-1-yl]acetamidein the procedure of Example 23 is replaced withN-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carboethoxyvinyl)indol-1-yl]acetamidethen the product prepared isN-methyl-N-phenethyl-2-[4-benzyloxy-3-(2-carboxyvinyl)indol-1-yl]acetamideas a white powder. (m.p. 170°-174° C.)

Example 74 5-benzyloxy-3-(3-carbmethoxybenzoyl)indole

To a solution 5-benzyloxyindole (2.23 g, 10 mmol) in 5 ml oftetrahydrofuran (THF), cooled in an external ice bath, is added dropwisewith stirring 6.15 ml of a 2 molar solution of methyl magnesium bromidein diethyl ether. The resulting mixture is stirred for an additional 15minutes in the ice bath and a solution of 3-carbmethoxybenzoyl chloridein 10 ml of THF is added dropwise. The cooling bath is removed and thereaction mixture is stirred at room temperature for 18 hours. Water isthen added, followed by ethyl acetate. The layers are separated. Theorganic layer is dried (MgSO₄) and concentrated in vacuo. The residueobtained is purified by a silica gel column, eluting with a solventsystem of 25% ethyl acetate in hexane to give5-benzyloxy-3-(3-carbomethoxybenzoyl)indole. NMR confirms thisstructure.

Example 75 4-benzyloxy-3-carboethoxyphenylmethylindole

When 5-benzyloxyindole and 3-carbomethoxybenzoyl chloride in theprocedure of Example 74 are replaced by 4-benzyloxyindole and ethyl2-bromophenylacetate, respectively, then the compound prepared is4-benzyloxy-3-carboethoxyphenylmethylindole as an off-white powder.(m.p. 126°-128° C.)

Example 76 5-benzyloxy-3-(3-carboethoxy-2-propenyl)indole

When 3-carbmethoxybenzoyl chloride in the procedure of Example 74 isreplaced by ethyl 4-bromocrotonate then the compound prepared is5-benzyloxy-3-(3-carboethoxy-2-propenyl)indole which is a beige oil. NMRconfirms this structure.

Example 77N-methyl-N-phenethyl-2-[5-benzyloxy-3-(3-carbomethoxybenzoyl)indol-1-yl]acetamide

When 5-benzyloxyindole-3-carboxaldehyde in the procedure of Example 10is replaced by 5-benzyloxy-3-(3-carbomethoxybenzoyl)indole, then thecompound prepared isN-methyl-N-phenethyl-2-[5-benzyloxy-3-(3-carbomethoxybenzoyl)indol-1-yl]acetamide.This compound is recrystallized from ethyl acetate to give a beigecrystal. (m.p. 224°-230° C.)

Example 78N-methyl-N-phenethyl-2-(4-benzyloxy-3-carboethoxyphenylmethylindol-1-yl]acetamide

When 5-benzyloxyindole-3-carboxaldehyde in the procedure of Example 10is replaced by 4-benzyloxy-3-carboethoxyphenylmethylindole, then thecompound prepared isN-methyl-N-phenethyl-2-(4-benzyloxy-3-carboethoxyphenylmethylindol-1-yl)acetamide.

Example 79N-methyl-N-phenethyl-2-[-5-benzyloxy-3-(3-carboethoxy-2-propenyl)indol-1-yl]acetamide

When 5-benzyloxyindole-3-carboxaldehyde in the procedure of Example 10is replaced by 5-benzyloxy-3-(3-carboethoxy-2-propenyl)indole, then thecompound prepared isN-methyl-N-phenethyl-2-[5-benzyloxy-3-(3-carboethoxy-2-propenyl)indol-1-yl]acetamide.NMR confirms this structure.

Example 80N-methyl-N-phenethyl-2-5-benzyloxy-3-(3-carboxybenzoyl)indol-1-yl]acetamideN-methyl-N-phenethyl-2-[(4-benzyloxy-3-(1-carboxy-1-phenyl)methyl)indol-1-yl]acetamideN-methyl-N-phenethyl-2-[5-benzyloxy-3-(3-carboxy-2-propenyl)indol-1-yl]acetamide

In a procedure similar to that described in Example 23,N-methyl-N-phenethyl-2-[5-benzyloxy-3-(carboethoxybenzoyl)indol-1-yl]acetamideis hydrolyzed toN-methyl-N-phenethyl-2-[5-benzyloxy-3-(carboxybenzoyl)indol-1-yl]acetamideas a beige powder. (m.p. 224°-230° C.)

Similarily,N-methyl-N-phenethyl-2-(4-benzyloxy-3-(1-carboethoxy-1-phenyl)methylindol-1-yl)acetamideis hydrolyzed toN-methyl-N-phenethyl-2-(4-benzyloxy-3-(1-carboxy-1-phenyl)methylindol-1-yl)acetamideas a white crystal. (m.p. 201°-203° C.)

N-methyl-N-phenethyl-2-[5-benzyloxy-3-(3-carboethoxy-2-propenyl)-indol-1-yl]acetamideis hydrolyzed toN-methyl-N-phenethyl-2-[5-benzyloxy-3-(3-carboxy-2-propenyl)indol-1-yl]acetamideas an orange powder. (m.p. 150°-155° C. (dec.))

Example 81 5-phenoxyindole-3-carboxaldehyde

When N-methyl-N-phenethyl-2-(5-indolyloxy)acetamide in the procedure ofExample 6 is replaced with 5-phenoxyindole, then the product obtained is5-phenoxyindole-3-carboxaldehyde. NMR confirms this structure.

Example 82 5-phenylindole-3-carboxaldehyde

When N-methyl-N-phenethyl-2-(5-indolyloxy)acetamide in the procedure ofExample 6 is replaced with 5-phenyl-indole, then the product prepared is5-phenylindole-3-carboxaldehyde. NMR confirms this structure.

Example 83N-methyl-N-phenethyl-2-[(3-formyl-5-phenoxy)indol-1-yl]acetamide

When 5-benzyloxyindole-3-carboxaldehyde in the procedure of Example 10is replaced by 5-phenoxyindole-3-carboxaldehyde, then the compoundprepared isN-methyl-N-phenethyl-2-[(3-formyl-5-phenoxy)indol-1-yl]acetamide. NMRconfirms this structure.

Example 84

Following the procedure of Example 10 the following compounds may beprepared:

N-methyl-N-phenethyl-2-[(3-formyl-5-phenyl)indol-1-yl]acetamide;

N-methyl-N-phenethyl-2-[(4-bromo-3-formyl)indol-1-yl]acetamide; and

N-methyl-N-phenethyl-2-[3-formyl-4-(2-phenylvinyl)indol-1-yl]acetamide.

NMR confirms these structures.

Example 85 4-(2-phenylvinyl)indole

When indole-4-carboxaldehyde is treated with the anion prepared from 2.5molar equivalent of diethyl benzylphosphonate and sodium hydride, in aprocedure similar to that described in Example 22, then the productprepared is 4-(2-phenylvinyl)indole. NMR confirms this structure.

Example 86 4-(2-phenylvinyl)indole-3-carboxaldehyde

When 4-(2-phenylvinyl)indole is used in Example 6 the product preparedis 4-(2-phenylvinyl)indole-3-carboxaldehyde. NMR confirms thisstructure.

Example 87

Following the procedure of Example 22 the following compounds may beprepared:

N-methyl-N-phenethyl-2-[3-(2-carbethoxyvinyl)-5-phenoxyindol-1-yl]acetamide;

N-methyl-N-phenethyl-2-[3-(2-carbethoxyvinyl)-5-phenylindol-1-yl]acetamide;

N-methyl-N-phenethyl-2-[4-bromo-3-(2-carbethoxyvinyl)indol-1-yl]acetamide;and

N-methyl-N-phenethyl-2-[3-(2-carbethoxyvinyl)-4-(2-phenylvinyl)indol-1-yl]acetamide.

NMR confirms these structures.

Example 88

Following the procedure of Example 23 the following compounds may beprepared.

N-methyl-N-phenethyl-2-[3-(2-carboxyvinyl)-5-phenoxyindol-1-yl]acetamide;

N-methyl-N-phenethyl-2-[3-(2-carboxyvinyl)-5-phenylindol-1-yl]acetamide;

N-methyl-N-phenethyl-2-[4-bromo-3-(2-carboxyvinyl)indol-1-yl]acetamide;and

N-methyl-N-phenethyl-2-[3-(2-carboxyvinyl)-4-(2-phenylvinyl)indol-1-yl]acetamide.

NMR confirms these structures.

Example 89

Following the procedures of Examples 1-88 the following compounds may beprepared.

4-[(N-methyl-N-phenethyl)carbamoylmethyl]-1-benzyloxy-2-naphthoic acid(m.p. 55°-60° C.)

4-[(N-methyl-N-phenethyl)carbamoylmethyl]-8-benzyloxy-2-naphthoic acid(m.p. 181°-183° C.)

4-[(N-methyl-N-phenethyl)carbamoylmethyl]-8-phenyl-2-naphthoic acid(m.p. 175°-177° C.)

4-[(N-methyl-N-phenethyl)carbamoylmethyl]-8-phenyl-2-(2-carboxy)vinylnaphthalene(m.p. 159° C.(dec.))

2-(2-carboxy)ethyl-4-[(N-methyl-N-phenethyl)carbamoylmethyl]-8-phenyl-naphthalene(m.p. 79°-80° C.)

8-benzyloxy-2-(2-carboxy)vinyl-4-[(N-methyl-N-phenethyl)carbamoylmethyl]naphthalene(m.p. 168°-170° C.)

5-benzyloxy-3-(4-carboxy-1,2-butadienyl)-1-[(N-methyl-N-phenethyl)carbamoylmethyl]naphthalene(m.p. 91°-100° C.(dec.))

5-benzyloxy-3-(4-carboxybutyl)-1-[(N-methyl-N-phenethyl)carbamoylmethyl]naphthalene(m.p. 110°-113° C.)

1-[(N-methyl-N-phenethyl)carbamoylmethyl]-3-(2-methyl-2-carboxy)vinyl-5-benzyloxynaphthalene(m.p. 172°-176° C.)

5-benzyloxy-3-[(2-carboxy-2-ethyl)vinyl]-1-[(N-methyl-N-phenethyl)carbamoylmethyl]naphthalene(m.p. 77°-79° C.)

4-[(N-methyl-N-phenethyl)carbamoylmethyl]-8-(2-quinoline-2-ylmethoxy)-2-naphthoicacid (m.p. 184°-186° C.)

4-[(N-methyl-N-phenethyl)carbamoylmethyl]-8-(naphth-2-ylmethoxy)-2-naphthoicacid (m.p. 174°-176° C.)

4-[(N-methyl-N-phenethyl)carbamoylmethyl]-8-(pyridine-3-ylmethoxy)-2-naphthoicacid (m.p. 207°-209° C.)

5-benzyloxy-3-carboxy-1-[(N2hydroxy-N-phenethyl)carbamoylmethyl]-naphthalene(m.p. 195°-202° C.)

We claim:
 1. A compound of the formula ##STR28## where: R₁₂ is

    --(CH.sub.2).sub.d --D--(CH.sub.2).sub.e --E

where D is a chemical bond, O, --CH₂ or --(CH═CH)_(x) where x is 1 or 2and E is --COOR' or tetrazolyl where R' is hydrogen or C₁₋₆ alkyl; R₁₄is ##STR29## where A is --CH₂ or O; B is phenyl or substituted phenylwhere the substituents are C₁₋₆ alkyl, halo C₁₋₆ alkyl, C₁₋₆ alkoxy orhalo and R' is hydrogen or C₁₋₆ alkyl; R₁₈ is

    --(CH.sub.2).sub.f --(CH.sub.2).sub.g --G

where F is O or --CH₂ and G is phenyl or substituted phenyl where thesubstituents are C₁₋₆ alkyl, halo C₁₋₆ alkyl, C₁₋₆ alkoxy or halo; anda, b, d, e, f and g are independently 0-4; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1 which is4-[(N-methyl-N-phenethyl)-carbamoylmethyl]-8-benzyloxy-2-naphthoic acidor a pharmaceutically acceptable salt thereof.
 3. A compound accordingto claim 1 which is4-[(N-methyl-N-phenethyl)-carbamoylmethyl]-8-phenyl-2-naphthoic acid ora pharmaceutically acceptable salt thereof.
 4. A compound according toclaim 1 which is4-[(N-methyl-N-phenethyl)-carbamoylmethyl]-8-phenyl-2-(2-carboxy)vinylnaphthaleneor a pharmaceutically acceptable salt thereof.
 5. A compound accordingto claim 1 which is2-(2-carboxy)ethyl-4[-(N-methyl-N-phenethyl)carbamoylmethyl]-8-phenylnaphthaleneor a pharmaceutically acceptable salt thereof.
 6. A compound accordingto claim 1 which is8-benzyloxy-2-(2-carboxy)vinyl-4-[(N-methyl-N-phenethyl)carbamoylmethyl]naphthaleneor a pharmaceutically acceptable salt thereof.